Ferroptosis and Alzheimer’s disease: a new insight into neurodegeneration

Alzheimer’s disease (AD), a chronic and progressive neurodegenerative disorder, poses a significant threat to the health of the aging population. The pathological hallmarks of AD include the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) within the brain. While substantial neuronal loss has been consistently observed in AD, the precise mechanisms underlying neuronal elimination remain incompletely understood. As a distinct form of regulated cell death, the contribution of ferroptosis to AD pathogenesis and progression warrants further investigation. This review critically examines the amyloid cascade hypothesis within the context of AD, with particular emphasis on the molecular signatures of ferroptosis and their contributions to canonical AD pathogenesis and cognitive decline. We aim to provide an updated perspective on AD etiopathogenesis. Furthermore, we synthesize current therapeutic strategies targeting ferroptosis inhibition in AD, highlighting recent advances that hold significant implications for guiding present and future translational efforts.

1 Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and neuropsychiatric symptoms, representing one of the most critical global public health challenges of the 21st century (1). Currently, it is estimated that over 50 million individuals worldwide are living with AD, and this number is projected to triple by 2050, imposing a profound socioeconomic burden (2, 3). Despite more than a century of dedicated research, the core pathogenic mechanisms of AD remain incompletely understood. Current diagnosis still primarily relies on two canonical neuropathological hallmarks: extracellular Aβ plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated Tau protein (4, 5). However, therapeutic development targeting these pathways has faced repeated setbacks. Most clinical trials, including those involving the conditionally approved agent aducanumab, have failed to demonstrate unequivocal clinical benefit (6, 7). Although lecanemab has shown efficacy in slowing cognitive decline in early AD in clinical trials, its long-term safety, broad clinical relevance, and therapeutic accessibility require further validation (8, 9). These persistent challenges underscore the limitations of the traditional “amyloid cascade hypothesis” and necessitate a paradigm shift—from a single-protein-centric perspective towards a more systemic and integrated molecular network approach—to unravel the pathogenic origins of AD.

In this context, ferroptosis—a newly defined, regulated cell death modality driven by iron-dependent lipid peroxidation—has rapidly emerged as a frontier and focus in AD research (10, 11). This process is centrally characterized by intracellular iron overload that initiates the Fenton reaction, catalyzing massive reactive oxygen species (ROS) generation; this in turn triggers the accumulation of lipid peroxidation products (e.g., 4-hydroxynonenal), protein oxidative damage (including promotion of Aβ1–42 aggregation), and DNA strand breaks (12). Concurrently, glutathione (GSH) depletion coupled with functional inactivation of glutathione peroxidase 4 (GPX4) collapses the cellular antioxidant defense system. Morphologically, ferroptosis is distinguished from other cell death modalities by characteristic ultrastructural alterations such as mitochondrial cristae dissolution and outer membrane condensation (13, 14).

Ferroptosis, a regulated form of cell death, plays a significant role in various pathological conditions, including neurodegeneration, cancer, and ischemia–reperfusion injury (Figure 1) (15–17). Its connection to AD was first established through key pathological evidence: Sayre et al. demonstrated that transition metals such as iron and copper bound within Aβ plaques and neurofibrillary tangles contribute substantially to oxidative catalytic activity, laying the foundation for understanding metal-driven oxidative stress and ferroptosis in AD (18). Subsequent studies further revealed a stage-specific, reciprocal network linking iron dysregulation, ferroptosis, Aβ/tau pathology, and neuroinflammation—three core components of AD pathogenesis. To clarify the causal relationships and stage−dependent roles of these factors, we propose a conceptual framework for AD progression (1):Early AD (causal events): Disruption of cerebral iron homeostasis leads to regional iron accumulation, which primes neurons for ferroptosis through elevated ROS and impaired antioxidant defenses (2).Transitional AD (facilitative events): Ferroptotic stress promotes Aβ aggregation and tau hyperphosphorylation. In turn, Aβ enhances iron uptake via transferrin receptor 1, and phosphorylated tau suppresses GPX4 expression, forming a self−reinforcing loop. Concurrently, ferroptotic death releases DAMPs, activating glial cells and initiating neuroinflammation, which further impairs iron homeostasis and antioxidant capacity (3).Late AD (downstream events): Sustained ferroptosis contributes to widespread neuronal loss, while progressive Aβ/tau deposition and chronic neuroinflammation drive synaptic dysfunction, circuit disruption, and clinical cognitive decline (19).

Figure 1

Figure 1. Ferroptosis is associated with diseases of various tissues and organs throughout the body. This figure provides a panoramic overview of major human organ systems and their associated prototypical diseases, thereby contextualizing the broad implications of ferroptosis across a spectrum of multisystem disorders. Centered on the central nervous system, the brain (depicted on the left) is associated with neurodegenerative conditions including AD and Parkinson’s disease, which directly aligns with the established pathological role of ferroptosis in AD. The figure further encompasses organs such as the spinal cord, lungs, liver, pancreas, and bones, alongside systems including the eyes, immune system, heart, kidneys, gastrointestinal tract, and hematopoietic system, each paired with their clinically relevant disorders. Collectively, this illustration underscores ferroptosis as a conserved, regulated cell death pathway that contributes to the pathogenesis of diseases spanning multiple organ systems.

This review aims to systematically elucidate the central role of iron dyshomeostasis and the ferroptosis process it drives in the pathogenesis of Alzheimer’s disease. Based on an integrated analysis of evidence from post-mortem pathology, neuroimaging, and experimental models, we propose that neuronal ferroptosis triggered by cerebral iron overload may constitute an early critical event that initiates and propels the subsequent pathological cascade in AD. This article provides an in-depth analysis of the molecular mechanisms underlying ferroptosis and delineates its complex interactions with the core pathological hallmarks of AD. We advocate that future AD research must establish a comprehensive framework that integrates iron metabolism, oxidative stress, and Aβ/tau pathology to transcend the limitations of the traditional amyloid-centric hypothesis, thereby achieving a more holistic understanding of AD pathogenesis. Furthermore, this review critically evaluates current therapeutic strategies targeting the ferroptosis pathway, with the objective of providing a theoretical foundation for developing novel interventional approaches.

2 AD

In the early 20th century, German psychiatrist Alois Alzheimer, using silver-staining techniques on the brain tissue of a patient with cognitive decline, first described two hallmark lesions: extracellular senile plaques composed of β-amyloid deposits and intraneuronal neurofibrillary tangles (20). This discovery challenged the prevailing view of dementia as an inevitable consequence of aging. In 1910, his mentor, Emil Kraepelin, named the condition “Alzheimer’s disease,” emphasizing its distinct pathological nature independent of age. Based on the age of onset, AD is classified into early-onset AD (EOAD, <65 years) and late-onset AD (LOAD, ≥65 years). LOAD is predominantly associated with sporadic risk alleles, exhibiting both genetic and etiological heterogeneity, where genetic and environmental factors collectively modulate disease risk and progression rate. Among these, the APOE ϵ4 allele represents the most well-established and robust genetic risk factor for LOAD, significantly increasing disease susceptibility in carriers (21–23).

The traditional “amyloid cascade hypothesis” posits that Aβ oligomers are the central pathogenic initiators in AD. They are proposed to trigger the disease process by activating glial cells, impairing synaptic plasticity, and inducing neuronal toxicity. Subsequently, abnormal Tau phosphorylation further disrupts axonal transport, ultimately leading to neuronal death. Nevertheless, some clinical-pathological studies(postmortem brain tissue samples from AD patients) has revealed significant limitations in this theoretical framework (24). For instance, transgenic mice overexpressing APP develop Aβ deposits but fail to form typical neurofibrillary tangles or exhibit significant neuronal loss (25). Concurrently, clinical trials targeting Aβ or Tau (e.g., using aducanumab or gosuranemab) have yielded only limited cognitive benefits, falling short of expectations and further highlighting the inadequacy of the traditional hypothesis (26, 27). These findings collectively indicate that focusing solely on Aβ toxicity is insufficient to fully explain the mechanisms underlying neurodegeneration.

Given these limitations, the establishment of a conceptual model capable of integrating multiple pathological processes and elucidating their spatiotemporal dynamics becomes imperative. We propose an integrative framework centered on the “iron dyshomeostasis-ferroptosis” axis, aiming to transcend the traditional linear cascade hypothesis. This model posits that during the early stages of AD, particularly in the preclinical phase, cerebral iron overload—triggered by genetic factors (e.g., APOE ϵ4) or aging—along with the resultant oxidative stress, constitutes a key upstream event that initiates the pathological cascade. The interactions between ferroptosis and Aβ/Tau pathologies, along with its amplifying effects on neuroinflammation, will be elaborated in subsequent chapters.

In the late stages of the disease, these interconnected pathways—ferroptosis, Aβ deposition, Tau tangle formation, and chronic neuroinflammation—converge and synergize, culminating in extensive neuronal loss and synaptic failure. Within this framework, ferroptosis is not merely a downstream consequence of Aβ/Tau pathology but also an upstream driver and a sustained propagator throughout the disease continuum. This model provides a more systematic and dynamic perspective for understanding the progression of AD from a compensable early phase to an irreversible advanced stage, thereby laying a theoretical foundation for developing precision combination therapies tailored to different disease stages.

3 The molecular mechanisms of ferroptosis

3.1 Iron metabolism and ferroptosis

Iron homeostasis is maintained by a sophisticated network of absorption, transport, storage, and efflux (28, 29). Dysregulation of iron metabolism, particularly impaired Tf/TfR1 uptake leading to an elevated labile iron pool, constitutes a core mechanism of ferroptosis (Figure 2) (30, 31). Brain iron is primarily acquired via transferrin-bound iron and non-transferrin-bound iron pathways (32, 33). TfR1 mediates efficient iron transport across the blood-brain barrier, with distinct neural cell types employing specific uptake mechanisms. Neurons and microglia rely predominantly on the Tf/TfR1 pathway and DMT1-mediated NTBI uptake; oligodendrocytes utilize the H-ferritin receptor; and astrocytes employ a multifaceted strategy including Tf/TfR1, DMT1, and perivascular uptake (34, 35). Systemic iron homeostasis is regulated by hepcidin, which degrades ferroportin, the primary cellular iron exporter, thereby preventing oxidative damage from free iron (36, 37). Disruption of this homeostatic network, especially during critical developmental periods, can lead to persistent cognitive deficits (38, 39).

Figure 2

Figure 2. Molecular mechanisms of ferroptosis. Ferroptosis is primarily induced by iron-mediated lipid peroxidation. This schematic delineates the core molecular circuitry of ferroptosis, a regulated iron-dependent lipid peroxidation-driven cell death pathway, and its direct implications for AD pathogenesis. It maps three interconnected axes of ferroptosis (1): Iron dyshomeostasis, where extracellular iron import via TFRC, ferritinophagy, and lipophagy elevate labile iron pools, fueling Fenton reaction-mediated ROS production— a process amplified in AD by Aβ and tau-induced iron accumulation in neurons and glia (2). Lipid peroxidation cascades, in which ACSL4/LPCAT3-mediated PUFA phospholipid synthesis and ALOX/POR-driven oxidation generate toxic lipid hydroperoxides (LOOH), damaging neuronal membranes and accelerating Aβ/tau aggregation in AD (3). Antioxidant system collapse, where impaired cystine import (via SLC7A11/SLC3A2) and GSH depletion compromise GPX4-dependent peroxide detoxification— a critical vulnerability in AD brains.

Ferroportin 1 (Fpn), the sole known mammalian non-heme iron exporter, is widely distributed in neurons, astrocytes, oligodendrocytes, and brain microvascular endothelial cells and is crucial for murine embryonic development, forebrain patterning, and neural tube closure (40, 41). Studies indicate that Fpn expression is downregulated in AD mouse models and in the brains of AD patients (42, 43). Neuron-specific knockout of Fpn in the cortex and hippocampus induces AD-like hippocampal atrophy and memory impairment in mice (44). Subsequent rescue experiments have demonstrated that restoring Fpn expression ameliorates both ferroptosis pathology and memory function. Notably, both Fpn-knockout mice and AD model mice exhibit classic morphological and molecular hallmarks of ferroptosis. Gene set enrichment analysis of ferroptosis-related transcriptomic data further reveals that differentially expressed genes are significantly enriched in AD-associated gene sets (44). Intriguingly, Fpn mRNA levels remain unchanged in some AD mouse models, suggesting potential post-transcriptional dysregulation of Fpn. Collectively, these findings establish that Fpn dysregulation and subsequent ferroptosis play an important role in AD progression, offering novel targeted therapeutic strategies for the disease.

3.2 Lipid peroxidation in ferroptosis

A defining hallmark of ferroptosis involves the accumulation of lipid peroxidation, primarily driven by oxidative damage to polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) (45, 46). The molecular structure of PUFAs, featuring multiple oxidatively vulnerable double bonds in their carbon chains, renders them particularly susceptible to peroxidation within membrane phospholipids such as phosphatidylethanolamine (PE) and phosphatidylinositol (PI), establishing these lipids as primary targets (47, 48). Key regulatory roles in ferroptosis are played by acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3). ACSL4 specifically activates long-chain PUFAs, including arachidonic acid (AA) and adrenic acid (AdA), via conjugation to coenzyme A. LPCAT3 subsequently esterifies these activated PUFAs into membrane phospholipids, generating peroxidation-susceptible lipid pools such as PE-AA and PE-AdA (47, 48). Inhibition of this enzymatic cascade significantly reduces lipid peroxide accumulation, effectively blocking ferroptosis progression (49). Notably, ferroptosis induction strictly depends on PUFA incorporation into phospholipids, as free oxidized PUFAs lack cell death-inducing capacity (50). Related in vitro and in vivo (HeLa cell line and mouse heterotopic tumor model) research identifies protein kinase C βII (PKCβII) as a crucial molecular sensor of lipid peroxidation; it detects initial lipid peroxidation signals and amplifies the peroxidation cascade through ACSL4 phosphorylation, thereby positively regulating ferroptosis (51). These findings establish ACSL4 as a novel ferroptosis regulator and reveal promising therapeutic targets for ferroptosis-related pathologies.

APOE gene polymorphism (ϵ2/ϵ3/ϵ4) profoundly influences ferroptosis susceptibility and neurodegenerative progression by remodeling neural lipid metabolism networks. The high-risk APOEϵ4 allele impairs ABCA1-mediated cholesterol efflux, disrupting neuronal membrane cholesterol/phospholipid ratios and promoting abnormal accumulation of PUFA-enriched phosphatidylethanolamine (PUFA-PE) in the plasma membrane. These phospholipids readily undergo Fe²⁺-dependent lipid peroxidation, creating a pro-ferroptotic microenvironment (52, 53). Concurrently, APOEϵ4 downregulates SLC7A11 expression, limiting cystine uptake and further compromising GPX4-mediated antioxidant defenses. In contrast, the APOEϵ2 allele activates the Nrf2 pathway, inducing expression of FSP1 and GSH synthetase to reconstitute the coenzyme Q10-vitamin E antioxidant axis, thereby markedly reducing PUFA-PE peroxidation susceptibility (54). This genotype-dependent modulation of lipid metabolism not only underscores the critical role of APOE polymorphism in ferroptosis regulation but also provides molecular insights into differential neurodegenerative disease susceptibility across genotypes.

4-Hydroxynonenal (4-HNE), a characteristic end-product of ω-6 polyunsaturated fatty acid (e.g., arachidonic acid) lipid peroxidation, serves as a key molecular biomarker of ferroptosis (55). This highly reactive aldehyde contains strongly electrophilic carbonyl groups that selectively modify sulfhydryl and amino groups within presynaptic membrane proteins (such as synaptophysin and vesicular glutamate transporters), disrupting synaptic vesicle docking and exocytosis. Such modifications lead to aberrant neurotransmitter release and ultimately trigger cellular ferroptosis (56, 57). Beyond its direct cytotoxic effects during ferroptosis, 4-HNE may indirectly promote cell death by modulating intracellular signaling pathways or impairing mitochondrial function. Furthermore, 4-HNE readily forms covalent adducts with Aβ peptides through cross-linking reactions, accelerating amyloid fibril formation and pathological deposition – a process critically implicated in the pathogenesis of neurodegenerative disorders including AD (58).

Cumulatively, the core mechanism of ferroptosis involves synergistic amplification of lipid peroxidation cascades through multiple feedback loops. This process extends beyond mere accumulation of lipid peroxides, engaging a complex pathological network modulated by diverse regulatory factors. These insights advance our mechanistic understanding of ferroptosis and illuminate its potential connections to neurodegenerative pathologies. Future therapeutic strategies targeting ferroptosis-associated pathways may reveal promising avenues for treating neurodegenerative diseases.

3.3 Antioxidant defense systems in ferroptosis

3.3.1 GPX4/GSH axis

GPX4 serves as the central executor of ferroptosis defense, and its function relies on the cysteine-glutathione metabolic axis mediated by SLC7A11. The System Xc^- transporter composed of SLC7A11 imports extracellular cystine into cells while exporting glutamate through an antiport mechanism. This process is a crucial prerequisite for GSH biosynthesis and also an important molecular switch for ferroptosis initiation (59). The xCT subunit with its 12 transmembrane domains mediates substrate transport, while the single-pass 4F2hc subunit ensures membrane localization and complex stability (60). Widely distributed in the central nervous system, this antiporter exports glutamate and imports cystine (Cys₂) (61, 62). This exchange process represents a significant molecular trigger for ferroptosis initiation (45).

Intracellular cystine is reduced to cysteine, the key precursor for GSH synthesis, while NADPH from the pentose phosphate pathway supplies reducing equivalents for this antioxidant system. Through its thiol group (–SH), GSH neutralizes lipid peroxides and thus inhibits ferroptosis (63). Under pathological conditions, impaired cystine uptake depletes GSH, depriving GPX4 of essential reducing support and ultimately inducing ferroptosis. Therefore, GPX4 expression and activity can serve as sensitive biomarkers for monitoring ferroptosis progression (64).

Unlike antioxidant enzymes such as SOD and CAT that scavenge free ROS, GPX4 specifically targets lipid peroxidation products in the phospholipid bilayer of cell membranes (65). By consuming GSH, GPX4 reduces cytotoxic phospholipid hydroperoxides (PLOOH) to harmless phospholipid alcohols (PLOH), thereby blocking the lipid peroxidation chain reaction and maintaining membrane integrity (66).

This axis is closely associated with the occurrence and development of AD: there is a significant increase in oxidative stress and a decrease in GSH levels in the AD brain, leading to impaired GPX4 activity, massive accumulation of lipid peroxidation products in neuronal cell membranes, and accelerated neuronal ferroptosis. In addition, Aβ deposition and excessive tau phosphorylation in the brains of AD patients can further inhibit the expression of SLC7A11, exacerbating GSH depletion and GPX4 inactivation, and forming a vicious cycle of “oxidative stress-ferroptosis-AD pathological damage”. Targeted enhancement of GPX4 activity or restoration of GSH synthesis capacity can effectively reduce neuronal ferroptosis in the brains of AD model animals and improve cognitive dysfunction, suggesting that this axis is a potential therapeutic target for AD.

Through this specialized mechanism, GPX4 consumes GSH to catalytically reduce cytotoxic membrane phospholipid hydroperoxides (PLOOH) into harmless phospholipid alcohols (PLOH), directly interrupting the lipid peroxidation chain reaction and preserving membrane integrity. This catalytic process critically depends on the selenocysteine (Sec) residue at its active site, with selenium deficiency significantly impairing GPX4 enzymatic activity (67). As previously established, the cystine-GSH metabolic axis supplies essential reducing equivalents for GPX4 function, where system Xc^--mediated cystine uptake represents the rate-limiting step for GSH biosynthesis. Pharmacological inhibition of this pathway by agents such as erastin depletes GSH reserves, directly inactivating GPX4 through loss of reducing power and culminating in uncontrolled membrane lipid peroxidation (68).

3.3.2 Nrf2/ARE axis

Transcription factor Nrf2 is a core regulator of cellular oxidative stress responses. It drives the expression of downstream antioxidant genes by activating the ARE, thereby regulating antioxidant defense and ferroptosis processes (63). Nrf2’s functional coordination is achieved through its domains: C-terminal Neh1 and Neh3 mediate DNA binding and transactivation, respectively, while N-terminal Neh2 enables Keap1-dependent negative regulation via its ETGE and DLG motifs (69, 70). Neh4/5 recruits CBP to promote transcription—a process suppressed by the Neh7–RARα complex (71, 72). The serine-rich Neh6 domain governs ubiquitin-mediated degradation, further regulating Nrf2 stability (73).

Under basal conditions, Keap1 maintains Nrf2 at low levels through constitutive binding. Oxidative stress triggers conformational changes in Keap1 via cysteine residue modifications, disrupting Keap1-Nrf2 interaction (74). Electrophilic inducers similarly modify Keap1 cysteines to promote Nrf2 release (75, 76). Liberated Nrf2 translocates to the nucleus, heterodimerizes with small Maf proteins (MafF, MafG, or MafK in vertebrates), and binds ARE sequences to transactivate cytoprotective genes including heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1) (77, 78). Downstream genes regulated by the Nrf2/ARE axis include HO-1, NQO1, and iron metabolism-related proteins (FTH1, FTL, FPN1), etc.: HO-1 degrades pro-oxidative heme to produce bilirubin with iron-chelating activity, and NQO1 directly scavenges lipid free radicals; both jointly block the lipid peroxidation cascade (79). Iron metabolism proteins reduce intracellular iron accumulation to decrease ferroptosis susceptibility (80, 81). In addition, the autophagic adaptor p62 can bind to Keap1 to promote its autophagic degradation, and at the same time, it is transcriptionally upregulated by Nrf2-ARE signaling, forming a positive feedback regulatory loop to enhance axis function (82, 83).

In the AD pathological microenvironment, the function of the Nrf2/ARE axis is significantly abnormal: the upregulated expression of Keap1 in the brains of AD patients leads to increased Nrf2 degradation. Meanwhile, Aβ and hyperphosphorylated tau can directly inhibit the nuclear translocation and transcriptional activity of Nrf2, impairing the axis’s function in regulating antioxidant and iron metabolic balance. This functional defect exacerbates oxidative stress and neuronal ferroptosis in the AD brain, further promoting Aβ deposition and tau pathology. Conversely, activating Nrf2 can significantly reduce pathological damage in the brains of AD model animals and improve learning and memory abilities by enhancing antioxidant defense and inhibiting ferroptosis. Preclinical studies have shown that Nrf2 activators can exert neuroprotective effects in AD by restoring the function of this axis, highlighting its potential as a therapeutic target for AD.

3.3.3 FSP1-NADH-CoQ axis

Ferroptosis suppressor protein 1 (FSP1), alternatively termed AMID or PRG3, exhibits pleiotropic biological functions. Initially characterized as a mitochondrially localized pro-apoptotic factor, in vitro and in vivo experiment reveal that myristoylation-mediated translocation to the plasma membrane converts FSP1 into a potent ferroptosis inhibitor (84, 85). The core molecular mechanism involves NAD(P)H-dependent reduction of coenzyme Q10 (CoQ) to ubiquinol (CoQH₂), which directly quenches lipid radicals through its antioxidant activity (84). Beyond its classical CoQ reductase function, FSP1 additionally suppresses ferroptosis via repair of oxidatively damaged plasma membranes and activation of the noncanonical vitamin K cycle (86). These findings not only elucidate the sophisticated defense network orchestrated by the FSP1-NAD(P)H-CoQ axis but also provide novel conceptual frameworks for developing ferroptosis-targeted interventions.

FSP1 expression is directly transcriptionally regulated by Nrf2, while Nrf2’s downstream target NAD(P)H quinone dehydrogenase 1 (NQO1) cooperatively maintains the reduced state of CoQ10 (87). Conversely, the antioxidative effects generated by the FSP1-CoQ10 system mitigate oxidative stress, indirectly stabilizing Nrf2 protein levels (84). This reciprocal positive feedback regulation establishes a sustained cellular defense system via the Nrf2-FSP1-CoQ10 axis, providing critical compensatory protection particularly during GPX4 inactivation. Significantly, this pathway functionally synergizes with the vitamin E antioxidant system through complementary membrane lipid protection mechanisms, offering a rational basis for combination therapeutic strategies against ferroptosis-associated pathologies.

3.4 Mitochondria in ferroptosis

Mitochondria, central to eukaryotic cellular iron metabolism, maintain iron homeostasis primarily through heme and ferritin storage. Relevant cell experiments reveal that this unique iron sequestration capacity positions mitochondria as contributory organelles in regulating ferroptosis (88). In Friedreich’s ataxia (FRDA) models, mitochondrion-specific iron overload directly triggers ferroptosis, while the mitochondrially targeted antioxidant XJB-5–131 significantly mitigates this process through chelation of labile iron (89). Further investigations demonstrate that mitochondrial-specific iron-sulfur (Fe-S) cluster biogenesis also modulates ferroptosis susceptibility. These findings collectively establish mitochondria as indispensable regulators within the ferroptosis network (90, 91).

Mitochondrial fatty acid oxidation generates acetyl-CoA, a major substrate for the TCA cycle. This process yields NADH and FADH₂, which provide electrons to the electron transport chain (ETC). Oxidative phosphorylation (OXPHOS) depends on iron ions as essential cofactors in ETC complexes, including cytochrome c oxidase, where they participate directly in electron transfer and oxygen reduction. Concurrently, elevated mitochondrial iron promotes peroxidative damage through Fenton-type reactions, ultimately triggering ferroptosis (88, 92). Moreover, mitochondrial iron overload inhibits Fe-S cluster-dependent enzymes such as aconitase 2, leading to the accumulation of metabolites like succinate. Excess succinate drives reverse electron transfer at complex I, while impaired α-ketoglutarate dehydrogenase activity limits NADPH regeneration. Together, these alterations weaken cellular antioxidant capacity (93). The resulting interplay between metabolic dysregulation and oxidative stress establishes a self-amplifying cycle, rendering ferroptosis largely irreversible once initiated.

Significantly, cardiolipin (CL), enriched in mitochondrial inner membranes with exceptionally high PUFA content (>80%), serves as a preferred target for peroxidation during ferroptosis (94). Under ROS attack, CL readily undergoes non-enzymatic peroxidation, leading to molecular degradation, double-bond reduction, increased hydrophilicity, and altered negative charge density. These modifications impair essential biological processes including electron transport, TCA cycling, and iron metabolism (95). Significantly, cardiolipin peroxidation products (e.g., hydroxyalkenal-modified CL) act as specific signaling molecules promoting cytochrome c (Cyt c) dissociation from the inner membrane and subsequent cytosolic release, constituting a event in mitochondrial apoptosis initiation.

In summary, dysregulated mitochondrial iron metabolism, ETC dysfunction, and cardiolipin peroxidation collectively regulate ferroptosis execution. Targeting mitochondrion-specific pathways—such as ETC inhibition, cardiolipin protection, or iron chelation—demonstrates anti-ferroptotic efficacy in neurodegenerative disease models, highlighting their therapeutic potential. These advances substantially advance our mechanistic understanding of ferroptosis while offering novel perspectives for targeted therapeutic approaches in neurodegeneration. Future research should prioritize elucidating mitochondrial coordination with other organelles (e.g., lysosomes) in ferroptosis and investigating how organelle-specific mitochondrial signatures influence ferroptosis susceptibility.

4 Ferroptosis and other forms of cell death

Ferroptosis is an iron-dependent form of cellular necrosis driven by the abnormal accumulation of lipid peroxides. Its core lies in the failure of the cellular antioxidant defense system, leading to the buildup of lipid ROS and ultimately disrupting plasma membrane integrity. To more clearly define this unique form of cell death and understand its complex roles in physiological and pathological processes, the following will systematically distinguish ferroptosis from three other important cellular events—apoptosis, necroptosis, and autophagy—in terms of their fundamental differences in core mechanisms, morphological features, and functional impacts.

4.1 Ferroptosis and apoptosis

Both are forms of regulated cell death, but they differ significantly in their execution mechanisms and morphological features. Apoptosis is a classic form of programmed cell death that relies on the cascade activation of caspase proteases. It plays an important role in maintaining tissue homeostasis and coordinating immune and defense functions (96, 97). Morphologically, apoptosis is characterized by cell shrinkage, chromatin condensation, and the formation of apoptotic bodies. Notably, the entire process occurs without the leakage of cellular contents and does not induce an inflammatory response. In contrast, ferroptosis does not depend on caspase activation. Its core driving factor is iron-mediated lipid peroxidation. Morphologically, ferroptosis mainly manifests as disruption of plasma membrane integrity, cytoplasmic vacuolization, and specific mitochondrial alterations (such as volume reduction, increased membrane density, and diminished or absent cristae), without the formation of apoptotic bodies. The release of cellular contents can trigger a local inflammatory response.

Under specific conditions, cells can switch from apoptosis to ferroptosis, a transition that enhances cellular sensitivity to apoptotic signals (98, 99). For example, when cancer cells develop resistance to apoptosis (e.g., due to high expression of BCL-2 protein or Caspase inactivation), inducing ferroptosis can serve as an effective alternative strategy to eliminate these cells. Additionally, some upstream stress signals (such as p53 activation) can trigger apoptosis and, under specific conditions (e.g., by inhibiting SLC7A11), promote ferroptosis (100, 101). Therefore, the intersection of ferroptosis and apoptosis pathways provides new insights for cancer therapy.

4.2 Ferroptosis and necroptosis

The distinction between ferroptosis and necroptosis lies mainly in their dependency mechanisms and triggering factors. Although both are forms of necrotic cell death that lead to plasma membrane rupture and inflammatory responses, their core mechanisms differ. Necroptosis is a programmed necrosis triggered by cytokines such as tumor necrosis factor (TNF) and relies on receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). Its key step involves kinase cascade-mediated activation and oligomerization of MLKL, which subsequently disrupts plasma membrane integrity (102). In contrast, ferroptosis is not associated with cytokine signaling. Its core depends on the presence of iron ions and the accumulation of lipid peroxidation and does not involve the RIPK1/RIPK3/MLKL pathway. Furthermore, necroptosis can be inhibited by specific agents such as necrostatin-1, whereas ferroptosis inhibition primarily relies on iron chelators (e.g., deferoxamine) or GPX4 activators, making their inhibitors entirely different.

Studies have shown that a key link between ferroptosis and necroptosis pathways is their sharing of some upstream stress sensors (103). For example, certain kinases or oxidative stress signals can simultaneously activate or regulate both pathways. Müller et al. further proposed that ferroptosis and programmed necrosis are complementary mechanisms of cell death (104). It is known that the key lipid metabolism enzyme ACSL4 serves as an indicator of ferroptosis, while MLKL, involved in the execution of necrosis, is a marker of programmed necrosis (102, 105). A deficiency in ACSL4 can lead to upregulation of MLKL expression, making cells more sensitive to ferroptosis (106). This evidence collectively suggests a dynamic compensatory relationship between the two pathways: inhibiting one cell death mechanism may lead to the activation of the other as compensation. Therefore, in therapeutic strategies, combined inhibition of both pathways may provide stronger tissue protection than inhibiting either one alone.

4.3 Ferroptosis and autophagy

Autophagy itself is a cellular self-protection mechanism. Its core is the autophagy-related gene (ATG)-regulated lysosomal degradation pathway, which degrades and recycles damaged organelles or proteins by forming autophagolysosomes to cope with stress and maintain homeostasis (107, 108). Under physiological conditions, autophagy plays a protective role in maintaining cellular homeostasis and may induce cell death only when it is excessively activated or when the autophagic flux is blocked. Under specific conditions, excessive or dysregulated autophagy can lead to cell death, but this is generally considered an “abnormal” consequence of autophagy.

In Vitro studies have revealed a new role for autophagy in cancer cell death, indicating that autophagy can trigger ferroptosis by initiating ferritin decomposition (109, 110). Specifically, autophagy can promote ferroptosis through selective degradation of ferritin (ferritinophagy) or antioxidant proteins. However, in most cases, autophagy remains a cell survival mechanism. Therefore, autophagy is not a specific death execution program; it primarily functions as an upstream regulatory factor to modulate ferroptosis, whereas ferroptosis is a well-defined death execution pathway culminating in lipid peroxidation. These findings reveal the intricate relationship and mutual regulatory mechanisms between ferroptosis and autophagy, providing new insights into understanding the complex network of cell death pathways and their interdependencies (110).

5 Ferroptosis and the core pathology of AD

5.1 Ferroptosis and Aβ plaques

Aβ misfolding and aggregation are key to AD pathology, with iron dysregulation promoting ferroptosis (111). Early AD involves iron accumulation in cortical and hippocampal areas (112), which disrupts iron homeostasis by altering key regulators: TfR1 and DMT1 decrease, while ferritin, ferroportin 1, and APP increase (113, 114). This enhances iron retention and shifts APP processing toward Aβ production (115). The aberrantly processed APP forfeits its chaperone-like function, further impairing ferroportin 1-mediated iron export and establishing a self-perpetuating cycle of iron dyshomeostasis (10, 116). Crucially, Soluble Aβ also binds Fe³⁺, reducing it to Fe²⁺ and accelerating plaque formation via iron-mediated oxidation (117). Together, these processes link iron dyshomeostasis, Aβ toxicity, and ferroptosis in driving neurodegeneration.

A bidirectional regulatory network exists between Aβ deposition and ferroptosis. Significant accumulation of lipid peroxides is observed in brain regions enriched with Aβ oligomers and in 4-HNE-positive areas of AD patients, indicating direct involvement of Aβ in the ferroptosis pathway (118). A core pathogenic mechanism involves Aβ oligomers embedding into the lipid bilayer of cell membranes, disrupting the spatial conformation of phospholipid dehydrogenases. This conformational impairment reduces dehydrogenation efficiency, non-enzymatically accelerating free radical chain reactions and lipid peroxidation (119). Pathological Aβ can also increase neuronal susceptibility to ferroptosis by activating the oxytocin receptor signaling axis (OXTR/PI3K/AKT pathway) (120). Conversely, the ferroptosis pathway exerts feedback on Aβ pathology. Activation of the upstream regulator peroxisome proliferator-activated receptor α (PPARα) induces the expression of ferroptosis suppressor protein 1 while simultaneously downregulating APP synthesis and inhibiting β-site APP cleaving enzyme 1 hydrolytic activity, effectively reducing Aβ oligomer generation (121). Furthermore, coenzyme Q10, an essential electron carrier in the FSP1 pathway, directly blocks lipid peroxidation chain reactions through its endogenous antioxidant properties and mitigates Aβ pathological burden in the cortex and hippocampus (122). Taken together, these findings illustrate a plausible and complex bidirectional interplay between Aβ pathology and ferroptosis-associated lipid peroxidation. However, a critical distinction must be made between mechanistic associations established in experimental systems and causative evidence in human disease. To date, conclusive evidence substantiating ferroptosis as a primary pathogenic driver in human AD is still lacking. Future research employing longitudinal biomarker studies and targeted interventional trials in human populations will be essential to validate its causal role and therapeutic relevance.

5.2 Ferroptosis and tau protein

Imbalanced brain iron homeostasis is mechanistically linked to tau hyperphosphorylation—a hallmark of AD pathology. Under physiological conditions, tau stabilizes microtubules and supports axonal transport. In AD, however, tau undergoes pathological hyperphosphorylation, leading to its dissociation from microtubules, aggregation into neurofibrillary tangles, and ultimately neuronal dysfunction (1).

Iron overload is hypothesized to exacerbate this process through several pathways. Experimentally, excess iron can impair insulin signaling, inhibit PI3K/Akt activity, and thereby enhance glycogen synthase kinase 3β-mediated tau phosphorylation at residues including Ser202, Thr205, and Ser396/404 (123). Iron may also promote cyclin-dependent kinase 5 activation via p25 binding, further driving tau phosphorylation (124). Additionally, iron-activated ERK/MAPK pathways may contribute to tau phosphorylation and neuroinflammatory cytokine release, suggesting a potential feedback loop between iron dysregulation, tau pathology, and inflammation (125, 126). Notably, reduced soluble tau levels have been associated with decreased expression of the iron exporter ferroportin 1, potentially worsening cerebral iron retention (127).

Phosphorylated tau may also intersect with lipid peroxidation processes relevant to ferroptosis. In AD models, phospho-tau colocalizes with lipid rafts enriched in polyunsaturated fatty acids, and ω-6 fatty acids such as arachidonic acid have been shown to promote tau oligomerization (128, 129). More critically, phosphorylated tau can electrostatically interact with anionic phospholipids, potentially destabilizing membranes and amplifying lipid peroxidation via NADPH oxidase activation (e.g., NOX2), thereby linking tau pathology to ferroptotic membrane damage (130).

While these experimental observations outline a plausible network connecting iron dysregulation, tau pathology, and ferroptosis, it is essential to distinguish between mechanistic associations established in model systems and causative evidence in human disease. Current support for ferroptosis as a primary driver of AD pathogenesis remains largely correlative, relying on post-mortem analyses, animal models, and in vitro data. Conclusive evidence from longitudinal clinical studies or targeted interventional trials in humans is still lacking. Thus, the role of ferroptosis in human AD—particularly as an initiating pathogenic event—requires further validation through clinically integrated research approaches.

5.3 Ferroptosis and neuroinflammatory plaques

5.3.1 Microglial cells

Microglia, the resident immune cells of the central nervous system, constitute approximately 10–12% of total brain cells and play a significant role in maintaining immune surveillance and neural homeostasis (131, 132). Beyond their functions in pathogen clearance and metabolic waste removal, microglia actively support neurodevelopment, synaptic plasticity, and neuroprotection (133, 134). It is important to note, however, that while most in vivo studies support a neuroprotective role for activated microglia, evidence from ex vivo or cultured microglial models suggests these cells may also exhibit neurotoxic potential. This phenotypic transition—from a protective, surveillant state to a pro-inflammatory and potentially detrimental phenotype—represents a key mechanism underlying neuroinflammation and neurodegeneration in AD.

5.3.1.1 Microglial and ferroptosis

Elevated cerebral iron levels activate the NF-κB signaling pathway, initiating the classical pro-inflammatory phenotypic transformation of microglia (135). Concurrently, iron acts as a damage-associated molecular pattern that can be recognized by microglial Toll-like receptor family members (e.g., TLR4), further amplifying inflammatory signaling. In response to the extracellular high-iron milieu, activated microglia upregulate ferritin expression in an attempt to sequester iron. Paradoxically, this promotes intracellular iron retention and oxidative stress, exacerbating the inflammatory microenvironment (136). Ferritin is a cage-like protein complex composed of 24 H- and L-subunits, whose stoichiometry is dynamically regulated in microglia to meet functional demands. Studies show that in high-iron conditions, microglia specifically upregulate L-subunit expression, and ferritin expression is observed predominantly under pathological conditions of significant brain iron elevation (137). This upregulation of microglial ferritin is a direct response to excess free iron released during neuronal ferroptosis. When early tangle-bearing neurons undergo ferroptosis, the released free iron triggers neighboring microglia to initiate ferritin synthesis, aiming to lower extracellular iron concentration through intracellular sequestration (138, 139). Consequently, the spatial distribution of immunoreactive ferritin-positive microglia can serve as a biological marker for the degree of labile iron accumulation in the brain parenchyma (139).

Neurons and microglia differ in iron handling: neurons rely on iron for metabolic activity, while microglia normally use ferritin storage for neuroprotection. In AD, however, elevated brain iron drives microglia toward a ferroptosis-prone state, marked by upregulated heme oxygenase-1 and enhanced release of inflammatory mediators like IL-1β (140, 141). This shift further accelerates Aβ accumulation via NADPH oxidase activity (142). The resulting oxidative environment induces lipid peroxidation and DNA damage, while activating MAPK/NF-κB signaling to promote amyloid precursor protein expression and impair Aβ clearance. Heme breakdown by HO-1 releases free iron, directly fueling iron-dependent peroxidation (140, 141). Together, iron and oxidative mediators activate the NLRP3 inflammasome, increasing IL-1β release and establishing a self-amplifying loop linking iron overload, neuroinflammation, and ferroptosis (18).

Activated immune pathways can positively regulate the susceptibility of microglia to ferroptosis and amplify their neurotoxicity. For instance, the activation of NF-κB and NLRP3 pathways leads to massive cytokine release (143). These cytokines, by inhibiting neuronal system Xc^- function and activating ACSL4, synergistically drive neuronal membrane lipid peroxidation and directly induce neuronal ferroptosis. Activated microglia can also generate potent oxidants like peroxynitrite, which inhibit key anti-ferroptotic proteins such as GPX4 and SLC7A11, dismantling the antioxidant defense systems of both the microglia themselves and neighboring neurons. Ultimately, ferroptotic microglia release damage-associated molecular patterns (DAMPs), including free iron, oxidized phospholipids, and HMGB1 (140, 144). These DAMPs can be sensed by surrounding viable microglia via pattern recognition receptors like TLRs, thereby re-initiating a new cycle of immune activation and inflammatory response.

5.3.1.2 Microglia and AD

The pathological significance of activated microglia in the brains of AD patients was first systematically described by McGeer and colleagues in 1987, a discovery that ignited extensive investigation into their potential role in neurodegenerative progression. The traditional view posits that microglia activated around senile plaques accelerate disease progression by releasing ROS, neurotoxins, and pro-inflammatory cytokines, thereby directly linking Aβ deposition to neurodegeneration (145, 146). Studies confirm that ferritin-positive microglia can emerge during the preclinical stage of LOAD. Their numbers increase with age and they form clusters around blood vessels and within senile plaque regions (147, 148). The density of these cells positively correlates with the severity of tau pathology, and their clustered aggregation is often a harbinger of neuritic plaque formation (149, 150). Consequently, microglia are regarded as key immune effector cells that drive the maturation of Aβ plaques and exacerbate the development of neurofibrillary pathology (151).

5.3.1.3 Microglial atrophy and AD

The recently proposed concept of “microglial atrophy” describes characteristic structural alterations in these cells during aging, including somatic shrinkage and process reduction (152). This phenotype is closely associated with upregulated intracellular ferritin expression, elevated brain iron levels, and oxidative stress. Data from AD patients and aged animal models demonstrate a significant decline in Aβ clearance capacity in senescent microglia (153, 154). This indicates that impaired microglial phagocytic function is a significant component of AD pathogenesis and suggests that restoring their homeostatic function through targeted intervention could be a potential therapeutic strategy (152).

In late-stage AD brain tissue, most microglia appear in a quiescent or dystrophic state, lacking classic activation markers such as soma hypertrophy. Similarly, microglia surrounding early neuronal ferroptosis events triggered by tau pathology frequently show no typical activation or phagocytic response. This functional deficit contrasts sharply with the normal physiological role of microglia, which is to rapidly respond to neuronal injury signals and clear cellular debris. This functional loss may stem from age-related phagocytic exhaustion and the direct toxicity of iron-rich Aβ and tau aggregates toward microglia (155) Furthermore, prior cell culture studies confirm that amyloid exposure accelerates microglial senescence (156). Based on this, we can hypothesize that iron-mediated oxidative toxicity may specifically damage microglia, thereby inhibiting their capacity to clear pathological proteins.

Despite showing atrophic damage, ferritin-positive microglia can maintain basic functions, a resilience attributed to their unique oxidative stress tolerance (157). These cells possess a hierarchical antioxidant system comprising superoxide dismutase, catalase, and glutathione peroxidase, and they maintain higher basal glutathione levels than neurons and astrocytes (157). This intrinsic antioxidant advantage enables microglia to preserve functional integrity under oxidative pressure (158, 159). Further research shows that lipopolysaccharide and interferon-γ stimulation can reduce glutathione levels in microglia, which inversely confirms the critical role of high glutathione reserves in their antioxidant capacity under resting conditions (160). Therefore, in the oxidative stress environment of AD, microglia can achieve self-preservation and functional maintenance by dynamically upregulating their antioxidant defenses.

While experimental understanding continues to advance, the precise causal relationship between microglial activation, neuroinflammation, and Alzheimer’s disease progression in humans remains to be fully established. It is noteworthy that although dysregulated microglial function is closely associated with AD pathology—including interactions with Aβ, tau, and emerging processes such as ferroptosis—the hypothesis that microglia-driven neuroinflammation or related ferroptosis serves as an initiating or central driver of human AD still relies predominantly on correlative and preclinical evidence. Further longitudinal clinical studies and targeted interventional trials are necessary to determine whether modulating microglial activity or ferroptosis can meaningfully alter the disease course in AD patients.

5.3.2 Astrocytes

The entry of dietary iron into the central nervous system is contingent upon blood-brain barrier(BBB) integrity, which is frequently compromised in Alzheimer’s disease. Large-scale postmortem analyses indicate that cerebrovascular pathology occurs in approximately 80% of AD cases—a prevalence markedly higher than in other neurodegenerative disorders such as Parkinson’s disease, frontotemporal dementia, and Lewy body disease—highlighting a potentially distinctive role of vascular dysfunction in AD pathogenesis (161).

Astrocytes, the predominant glial cell type in the brain, are strategically positioned at the BBB interface and contribute critically to cerebral homeostasis, neuronal support, and immune modulation (162, 163). In AD, astrocytes undergo activation and are implicated in both initiating and sustaining neuroinflammatory responses. They participate in the fine-tuned regulation of iron uptake, storage, and release—a process partly mediated by ceruloplasmin—to balance neuronal iron availability while limiting its toxicity (164–166). However, the molecular pathways governing astrocytic iron transport, including the contextual regulation of DMT1, ferroportin 1, and transferrin receptor 1, remain incompletely resolved and may vary with pathological conditions (167, 168). Under iron-rich conditions, astrocytes can enhance antioxidant defenses, such as glutathione synthesis, to maintain cellular viability (169). Yet, during prolonged inflammatory stimulation, they may adopt a pro-inflammatory phenotype, releasing substantial quantities of cytokines and thereby amplifying neuroinflammatory cascades (170, 171).

Although astrocyte dysfunction and iron dysregulation are increasingly recognized in AD pathology, their direct causal link to disease progression—and particularly to hypothesized central mechanisms such as ferroptosis—requires further validation in human contexts. Current evidence remains largely correlative or derived from preclinical models. Thus, while astrocytes appear to occupy a key intersection between iron metabolism and neuroinflammation in AD, conclusive evidence establishing ferroptosis as a primary pathogenic driver in human disease is still lacking. Future studies integrating longitudinal clinical data and mechanistic interventional approaches will be essential to clarify these relationships and their therapeutic relevance.

5.3.3 Brain capillary endothelial cells

Brain capillary endothelial cells (BCECs), a central component of the blood-brain barrier, regulate cerebral iron uptake through distinct yet possibly complementary transport models. Two principal mechanisms have been proposed: the classical transferrin-dependent pathway and the transcytosis model (39). The classical pathway describes a sequence in which transferrin-bound iron enters BCECs via receptor-mediated endocytosis. Within acidic endosomal compartments, Fe³⁺ is reduced to Fe²⁺, exported into the cytosol by divalent metal transporter 1 (DMT1), and subsequently released across the abluminal membrane via ferroportin 1 (FPN1), followed by re-oxidation through ceruloplasmin before entering the brain parenchyma (172, 173).

In contrast, the transcytosis model posits that the transferrin-iron complex undergoes vesicular trafficking across the endothelial cytoplasm without cytosolic release through DMT1 (174). This model is supported by observations of minimal DMT1 expression in BCECs, suggesting that iron may transit directly within endosomal vesicles to reach the brain interstitium (175, 176). These two models are not mutually exclusive and may operate under varying physiological or pathological conditions, though their interplay remains to be fully elucidated.

It should be noted that current understanding of iron transport mechanisms in brain capillary endothelial cells is predominantly derived from in vitro models or specific animal studies, and their applicability to intact biological systems and human physiological environments remains to be fully validated. Particularly noteworthy is the lack of direct human tissue evidence and dynamic functional studies regarding how these transport pathways are altered and contribute to pathology in neurodegenerative diseases such as Alzheimer’s disease. Furthermore, existing research has largely focused on transport mechanisms under physiological conditions, while in pathological contexts—such as impaired blood-brain barrier integrity or chronic inflammatory microenvironments—these transport patterns may undergo significant reprogramming, with regulatory networks likely far more complex than current models suggest.

6 Evidence of ferroptosis in AD

6.1 Imaging evidence

Recent advancements in neuroimaging have significantly advanced the diagnosis and research of AD. Multimodal imaging has become a cornerstone, with clinical guidelines recommending structural neuroimaging in cognitively impaired individuals to assess medial temporal lobe atrophy and rule out other pathologies (177, 178). Post-mortem studies provide the most direct evidence, demonstrating significant iron accumulation within glial cells surrounding Aβ plaques in the AD brain, suggesting iron overload as a key driver of plaque formation. For in vivo imaging, quantitative susceptibility mapping (QSM), an advanced MRI technique, enables precise quantification of regional brain iron deposition. Studies show that QSM-derived iron levels correlate significantly and negatively with cognitive function in AD patients, confirming the role of iron dysregulation in the disease mechanism (11, 179). Integrated analyses combining amyloid-PET with QSM further indicate that elevated cerebral iron load is closely associated with Aβ-related cognitive decline, suggesting a synergistic neurotoxic interaction between the two pathological processes.

Beyond conventional structural MRI and molecular imaging, emerging technologies such as diffusion tensor imaging (DTI), arterial spin labeling (ASL), and novel PET tracers targeting the cholinergic system or microglial activation provide unprecedented insights into AD pathophysiology (180). Although automated image analysis techniques require further refinement, these imaging advances not only deepen our understanding of ferroptosis-related mechanisms in AD but also lay the groundwork for developing early diagnostic and targeted therapeutic strategies (181, 182). Notably, QSM-based iron quantification holds strong potential to become a key component of future multi-modal AD biomarker panels.

6.2 Pathological evidence

Goodman first histochemically identified abnormal iron deposition in the cerebral cortex of AD patients in 1953 (183). Subsequent studies confirmed elevated iron levels in AD gray matter (184), with regional accumulation particularly evident in cognitive-related limbic and paralimbic structures such as the amygdala, hippocampus, and olfactory pathways (185). Recent evidence indicates that AD brains exhibit canonical ferroptotic pathology, which drives mitochondrial cardiolipin peroxidation, causes ultrastructural damage, impairs ATP synthesis, and ultimately triggers irreversible neurodegenerative decline (Figure 3) (186).

Figure 3

Figure 3. Molecular mechanisms of ferroptosis in brain microenvironment. Extracellular glutamate accumulates and inhibits the cystine-glutamate antiporter SLC7A11/SLC3A2, blocking cystine uptake and starving the cell of cysteine needed for glutathione (GSH) synthesis; simultaneously, transferrin receptor (TFRC) imports Fe³⁺ into endosomes where STEAP3 reduces it to Fe²⁺ that is released into the cytosol via DMT1/SLC11A2, and cytosolic chaperones PCBP1/2 deliver Fe²⁺ to ferritin or mitochondrial VDACs; NCOA4-mediated ferritinophagy degrades ferritin, liberating redox-active Fe²⁺ that fuels Fenton chemistry to generate hydroxyl radicals, which together with ALOX enzymes convert polyunsaturated fatty-acid phospholipids (AA/AdA-PE) to lipid hydroperoxides (AA/AdA-OOH-PE); because the GPX4-GSH axis is incapacitated by GSH depletion, these lipid peroxides cannot be reduced, accumulate, and ultimately rupture membranes, executing ferroptosis.

6.2.1 GSH/GPX4

Depleted glutathione levels in the hippocampus and frontal cortex are strongly associated with severe cognitive impairment in Alzheimer’s disease (18). In AD rat models, N-acetylcysteine exerts anti-lipid peroxidation effects by elevating brain GSH levels, with its neuroprotective mechanism linked to enhanced cellular and mitochondrial membrane stability (187, 188). Post-mortem brain tissue from AD patients and transgenic mouse models (e.g., APP/PS1, 5xFAD) consistently shows significant downregulation of glutathione peroxidase 4 protein expression, accompanied by characteristic ferroptotic morphological alterations such as mitochondrial shrinkage (189). As a key enzyme responsible for clearing peroxides, GPX4 inactivation can directly lead to hippocampal neuronal death. Experimentally, mice with conditional knockout of GPX4 in the cortex and hippocampus exhibit profound spatial memory deficits and hippocampal neurodegeneration (189).

Mechanistic studies reveal that lipoic acid can inhibit ferroptosis by downregulating transferrin receptor expression and upregulating GPX4, thereby protecting neurons involved in learning and memory and improving cognitive function (Figure 4) (190). This regulatory relationship is inversely validated at the molecular level: the GPX4 inhibitor RSL3 potently induces ferroptosis by binding to its active site, serving as a reliable experimental tool for studying ferroptosis in AD and directly establishing a causal link between GPX4 inhibition and AD pathology (191). Targeting the GPX4 pathway has proven effective in mitigating AD-associated ferroptosis. In both in vitro and in vivo models, ferroptosis inhibitors significantly reduce Aβ-aggregation-induced neuronal death and ameliorate memory deficits (44). Similarly, PPARα agonists alleviate lipid peroxidation and neuroinflammation by enhancing GPX4 transcription (192). These collective findings confirm that GPX4 dysfunction exacerbates AD progression by promoting ferroptosis. This not only deepens our mechanistic understanding of the disease but also highlights the significant therapeutic potential of modulating the GSH-GPX4 axis in AD intervention.

Figure 4

Figure 4. Mechanisms associated with ferroptosis in AD. APP is cleaved by β-secretase to produce Aβ oligomers that trigger hyperphosphorylation of Tau into neurofibrillary tangles (NFTs) and activate p53, which up-regulates CDKN1A and DPP4, represses SLC7A11, and thereby lowers GSH synthesis and inactivates GPX4; Aβ also promotes TfR1-mediated endocytosis of Fe³⁺ that is reduced to Fe²⁺ in endosomes and released via DMT1, and the resulting labile iron generates hydroxyl radicals through Fenton and Haber-Weiss reactions that enable ALOX12 to convert PUFA-containing phospholipids (PUFA-PL) to lipid hydroperoxides (PL-OOH); with the GSH-GPX4 antioxidant axis collapsed and lipid ROS relentlessly accumulating, neuronal membranes undergo oxidative demolition that triggers ferroptosis and accelerates Alzheimer’s disease progression.

6.2.2 Biomarkers of lipid peroxidation

Lipid peroxidation, a core pathological hallmark of ferroptosis, manifests prominently in AD. Studies using the 5xFAD transgenic mouse model demonstrate significantly elevated levels of lipid peroxidation end products (MDA, 4-HNE) and secondary products like lysophospholipids in brain tissue (189). This phenomenon is further validated in clinical samples, where MDA and 4-HNE levels are markedly increased in the brain tissue, cerebrospinal fluid, and blood of AD patients compared to healthy controls, with post-mortem analyses providing additional confirmation (193). Notably, 4-HNE can activate the PPARγ pathway, suppressing PGC-1α-mediated mitochondrial biogenesis and reducing local ATP supply at synapses, thereby impairing plasticity mechanisms such as LTP (56) Simultaneously, the electrophilic properties of 4-HNE facilitate its formation of adducts with synaptic proteins (e.g., synapsin I, PSD-95), directly disrupting synaptic ultrastructure (194). Under this dual assault of energy metabolism impairment and membrane structural damage, synapses emerge as vulnerable early targets of ferroptosis, providing a mechanistic basis for the cognitive alterations observed in the preclinical stages of AD.

Critically, key cellular metabolic pathways—including thiol metabolism, fatty acid metabolism, and mitochondrial respiration—directly influence cellular susceptibility to lipid peroxidation and ferroptosis (195). In transgenic AD mouse models, the fatty acid synthase inhibitor CMS121 prevents excessive lipid peroxidation and inflammation while mitigating cognitive decline (196). Mitochondrial aldehyde dehydrogenase (ALDH2) ameliorates dual cardiac and neurological dysfunction in APP/PS1 mice by degrading toxic aldehydes and inhibiting ACSL4-mediated ferroptosis (197).

6.3 Classical genetic risk factors for AD

6.3.1 APOEϵ4

APOE represents one of the most prominent genetic risk factors for AD, with its ϵ4 allele (APOEϵ4) demonstrating a strong association with disease pathogenesis and progression. In mouse models has established that APOE suppresses HMG-CoA reductase within the cholesterol synthesis pathway, leading to substantial intracellular accumulation of acetyl-CoA, the precursor for cholesterol biosynthesis (198). Given that acetyl-CoA also serves as the precursor for PUFA synthesis, its excessive accumulation provides the substrate foundation for lipid peroxidation, thereby fostering a pro-ferroptotic microenvironment. Clinical cohort studies confirm that cerebrospinal fluid levels of lipid peroxidation markers (e.g., MDA, 8-OHdG) are significantly elevated in APOEϵ4 carriers compared to APOEϵ2 carriers, exhibiting a strong positive correlation with the rate of hippocampal atrophy (199). This underscores the therapeutic potential of targeting the APOE-lipid metabolism axis to disrupt the ferroptotic cascade in AD. Furthermore, APOEϵ4 directly promotes cerebral iron accumulation—positively correlated with cognitive decline—thereby amplifying neurotoxicity and contributing significantly to AD incidence (200, 201).

6.3.2 IREB2

IREB2, an iron-regulatory protein, maintains cellular iron homeostasis by binding to iron-responsive elements and controlling the expression of iron-metabolism genes (202). Loss-of-function mutations in IREB2 impair its inhibition of transferrin receptor 1 expression. Genetic variations in IREB2 have been associated with increased Alzheimer’s disease risk, underscoring its role in AD pathogenesis (203).

6.3.3 PSEN

Mutations in the PSEN1 or PSEN2 genes, associated with familial Alzheimer’s disease, disrupt the maturation of selenocysteine tRNA, leading to impaired cellular selenium uptake. Given that GPX4 is an essential selenoprotein whose activity is wholly dependent on selenium bioavailability, these mutations result in a progressive decline in GPX4 expression. This severely compromises the neuron’s capacity to eliminate lipid peroxides, ultimately driving neurons toward ferroptosis (204).

6.4 Epigenetic modifications

Epigenetic modifications serve as an interface between the genome and the external environment. Alterations in external conditions—such as dietary factors, chemical exposures, and psychological stressors—or cellular stress can induce changes in epigenetic marks, leading to gene transcription activation or silencing. These modifications critically regulate fundamental cellular processes including normal growth, development, and the maintenance of gene function. Key epigenetic regulatory mechanisms implicated in the onset and progression of neurodegenerative diseases encompass DNA methylation, histone modifications, and RNA editing (205).

6.4.1 Histone modifications

The activity of β-site APP cleaving enzyme 1 (BACE1), a contributory enzyme for Aβ generation, is transcriptionally regulated by histone acetylation. Specifically, elevated H3 acetylation within the BACE1 promoter enhances its expression, thereby accelerating Aβ deposition (206, 207). Concurrently, aberrant acetylation of tau protein impedes its degradation, promoting neurofibrillary tangle formation and undermining microtubule stability during AD progression. Furthermore, AD brains exhibit dysregulated histone methylation patterns, including alterations in H3K4me3 levels (208). Notably, the methyltransferase G9a catalyzes H3K9 methylation to upregulate key ferroptosis-suppressor genes such as GPX4 and SLC7A11, which may confer neuroprotection in AD (209). n a complementary manner, the demethylase KDM3B inhibits ferroptosis by removing H3K9 methylation marks, thereby enhancing SLC7A11 expression (210). These insights highlight the critical role of histone methylation in modulating ferroptosis pathways. Additionally, histone ubiquitination, exemplified by H2Bub1, acts as a prerequisite for establishing H3K4me3 and H3K79me3 marks and further fine-tunes ferroptosis through the regulation of SLC7A11 and related gene expression (211).

Nevertheless, current research establishing a direct link between histone modifications and ferroptosis in AD remains limited, with most evidence being indirect. Future investigations should integrate animal models and in vitro systems to systematically analyze the dynamic relationship between ferroptosis biomarkers and specific histone modification patterns (e.g., H3K9me3, H3K27me3) across different stages of the disease. Such studies hold significant promise for informing the development of novel therapeutic strategies and providing critical frameworks for treatment efficacy evaluation.

6.4.2 DNA methylation

Aberrant DNA methylation constitutes a significant epigenetic mechanism in neurodegenerative disorders (212). This modification primarily occurs within CpG islands (500–1000 bp regions with >60% C/G content) located in gene promoter regions. Catalyzed by DNA methyltransferases (DNMT1, DNMT2, DNMT3a, DNMT3b), it involves the transfer of a methyl group from S-adenosylmethionine (SAM) to the 5’ carbon position of cytosine residues, subsequently silencing gene expression by impeding transcription factor binding. In AD, age-associated declines in DNMT1 and DNMT3a2 expression contribute to abnormal methylation of memory-related genes (e.g., reelin), triggering cognitive dysfunction (213, 214). Human studies further demonstrate DNMT3a involvement in improving cognitive function in patients with mild cognitive impairment (215). Notably, reduced methylation levels within the APP promoter region promote Aβ generation. Aβ itself can induce global genomic hypomethylation while concurrently promoting hypermethylation of the neprilysin (NEP) promoter, establishing a self-perpetuating pathological cycle (216, 217). GPX4, a critical regulator of ferroptosis, exhibits significantly reduced expression in AD neurons. This observation presents a potential parallel to findings in cancer research, where DNA methylation directly governs GPX4 expression (218). While insights from oncology provide valuable clues for understanding ferroptosis regulation in AD, the distinct pathological microenvironment of AD—characterized by Aβ deposition, tau pathology, and chronic neuroinflammation—suggests that these epigenetic regulatory mechanisms likely exhibit disease-specific features. Consequently, direct investigations within AD models and patient cohorts are essential to validate the precise mechanistic role of DNA methylation in regulating ferroptosis during neurodegeneration.

6.4.3 Non-coding RNA

microRNA (miRNA) are single-stranded non-coding RNAs typically composed of 19–25 nucleotides. These molecules play critical regulatory roles in diverse biological processes, including metabolism, neurodevelopment, synaptic plasticity, cell death, and other neurobiological functions. In the cerebrospinal fluid of AD patients, dysregulation of numerous miRNAs correlates with disease progression. Notably, upregulated expression of miR-9, miR-125b, miR-146a, and miR-155 promotes neuroinflammation by suppressing complement factor H (CFH) expression (219). Additionally, miR-9 contributes to AD pathogenesis by inducing ferroptosis through targeted inhibition of SLC7A11, thereby blocking GSH synthesis, and additionally participates in regulating NFTs formation (220). Similarly, miR-137 activates ferroptosis by downregulating SLC1A5, leading to impaired cysteine uptake and consequent disruption of GSH synthesis (221). Insights from oncology research, demonstrating that miR-522 inhibits lipid ROS accumulation and suppresses ferroptosis by targeting ALOX15, offer valuable perspectives for understanding ferroptosis regulation in AD (222). While these findings establish important connections, direct evidence specifically linking miRNA-mediated regulation to neuronal ferroptosis in AD remains limited. Future research should prioritize elucidating the roles of specific miRNAs in driving ferroptosis within AD neurons and evaluating their therapeutic potential.

6.5 Clinical and translational evidence: limitations and prospects

Although preclinical and pathological studies provide substantial support for the role of ferroptosis in Alzheimer’s disease, direct human evidence and clinical translational research remain significantly insufficient, representing a critical bottleneck in current investigations. The main limitations are reflected in the following aspects:

6.5.1 Lack of a specific in vivo biomarker system

Currently, no biomarker profile has been established that can specifically and dynamically reflect the ferroptosis process in vivo. Although lipid peroxidation products (e.g., 4-HNE, MDA) and systemic iron parameters are altered in bodily fluids of AD patients (e.g., cerebrospinal fluid, blood), these markers lack disease and cell death modality specificity, as similar changes can occur in other neurodegenerative disorders or systemic pathological conditions. Therefore, developing and validating biomarkers that directly indicate neuronal ferroptosis—such as specific oxidized phospholipid profiles, ferroptosis-related proteins (e.g., released HMGB1, modified GPX4), or their metabolic fragments—is crucial for enhancing clinical diagnostic and therapeutic monitoring capabilities.

6.5.2 Immaturity of in vivo imaging techniques

Existing neuroimaging technologies can indirectly reflect iron deposition (e.g., QSM) or amyloid burden (e.g., Aβ-PET) but are currently unable to directly and non-invasively visualize the spatiotemporal dynamics of iron-dependent lipid peroxidation, loss of membrane integrity, or ferroptosis-associated mitochondrial morphological changes. Future efforts should focus on developing novel imaging probes or methodologies, such as PET tracers or functional MRI techniques targeting active lipid peroxides, redox imbalance, or ferroptosis-specific membrane damage, to enable quantitative and localized analysis of ferroptosis in the living human brain.

6.5.3 Extremely limited clinical intervention

Most current evidence derives from preclinical models, while interventional clinical trials specifically designed to target the ferroptosis pathway in AD patients remain scarce. Although strategies such as iron chelators (e.g., deferoxamine), antioxidants (e.g., N-acetylcysteine), and GPX4 activation demonstrate neuroprotective potential in animal and cellular models, their safety, tolerability, blood-brain barrier permeability, and ability to modulate disease progression in humans have not been systematically validated. Advancing Phase II/III clinical trials targeting key nodes of ferroptosis (e.g., iron metabolism, GPX4 function, lipid peroxide clearance) is essential to confirm its therapeutic value and translational potential.

In summary, although the ferroptosis hypothesis is mechanistically compelling and supported by evidence from models and post-mortem tissue, its role as a primary therapeutic target in human Alzheimer’s disease remains to be validated. Future research must prioritize the development of specific in vivo biomarkers, the advancement of pathophysiology-targeted imaging tools, and the implementation of well-designed clinical trials targeting key nodes of the ferroptosis pathway. Only through such translational efforts can we determine whether modulating ferroptosis represents a viable strategy for delaying or preventing the progression of Alzheimer’s disease.

7 Therapeutic strategies and clinical translation

With the deepening understanding of ferroptosis mechanisms, an increasing number of molecular targets have been identified as closely associated with the pathological progression of AD. These key molecules not only provide novel perspectives for elucidating AD pathogenesis but also offer potential targets for developing new neuroprotective agents (223). Currently, targeted neuroprotective drugs acting on ferroptosis pathways are under progressive development, with iron chelators, antioxidants, and free radical scavengers being extensively investigated to achieve neuronal protection through modulation of ferroptosis processes (224). This section summarizes the current research status of reported ferroptosis-related pharmacological agents, analyzing their mechanisms of action and therapeutic effects in AD models, aiming to provide theoretical foundations and structural references for future anti-AD drug design based on ferroptosis mechanisms (Table 1).

Table 1

Table 1. Therapeutic strategies targeting ferroptosis and their mechanisms of action.

7.1 Iron chelators

7.1.1 Preclinical stage

Natural and synthetic iron chelators in preclinical development exhibit neuroprotective potential by modulating cerebral iron dyshomeostasis, though their translational value requires further validation. The natural polyphenol curcumin provides broader neuroprotection; beyond efficient iron chelation, its phenolic structure directly inserts into the Aβ folding core, inhibiting oligomer formation (225). Animal models demonstrate that curcumin treatment dissociates existing Aβ plaques in the mouse hippocampus and significantly inhibits tau hyperphosphorylation at Ser202/Thr205 in the dentate gyrus (226, 227). However, curcumin faces inherent limitations including poor bioavailability and inefficient BBB penetration, which hinder its clinical translation. Synthetic chelators like desferrioxamine (DFO) have been extensively validated in preclinical models: studies confirm DFO significantly reduces free iron concentrations in the hippocampus of APP/PS1 mice, concurrently decreasing Aβ plaque burden and improving cognitive function (228). Nevertheless, DFO’s clinical applicability is constrained by poor BBB penetration and non-oral administration route, prompting the development of modified delivery systems(e.g., DFO-gold nanoparticle conjugates, NCT05022472) currently under preclinical optimization.

7.1.2 Clinical stage

Deferiprone (DFP) represents a promising clinical-stage iron chelator with oral absorbability and BBB permeability, demonstrating a favorable safety profile with low systemic toxicity, which positions it as a viable strategy for countering iron dyshomeostasis and ferroptosis in AD therapeutics (229). Despite its translational advantages, clinical application of DFP and other iron chelators is not without risks: neutropenia remains a serious adverse event frequently observed in patients receiving iron chelation therapy (230). Additionally, given their systemic impact on iron homeostasis, regular monitoring of iron metabolism and vital organ functions—particularly hepatic and renal systems—is essential to minimize adverse events and ensure therapeutic safety. Ongoing clinical research focuses on optimizing brain-targeted delivery (e.g., NCT05022472, a trial evaluating DFO-gold nanoparticle conjugates) and developing structural analogs (e.g., CNB-001) to enhance efficacy while reducing off-target effects.

7.2 Antioxidants

7.2.1 Preclinical stage

Phillyrin A, a naturally occurring iridoid glycoside isolated from Forsythia suspensa, has garnered attention for its broad biological activities including anti-inflammatory, neuroprotective, and ferroptosis-inhibitory effects (231, 232). In vitro studies demonstrate its efficacy in mitigating Aβ-induced neuroinflammation and apoptosis in hippocampal slices (233), while HT22 cell models confirm phillyrin A counteracts erastin-induced ferroptosis by elevating GSH content, reducing ROS and malondialdehyde (MDA) levels. Preclinical animal studies further validate its neuroprotective potential: phillyrin A improves learning and memory in senescence-accelerated mice, activates the Nrf2 signaling pathway in APP/PS1 mice, upregulates antioxidant proteins (NQO1, GPX4), and normalizes cerebral iron content through modulation of TFRC, DMT1, FTH, and FTL gene expression (234). Ultrastructural analyses also indicate its ability to mitigate erastin-triggered ferroptotic mitochondrial alterations (e.g., shrinkage and cristae disruption). However, phillyrin A’s clinical translation is currently limited by insufficient data on BBB penetration efficiency, long-term safety, and optimal dosing regimens.

7.2.2 Clinical stage

N-acetylcysteine (NAC), an acetylated derivative of cysteine naturally present in foods like onions, is a clinical-stage antioxidant with well-characterized BBB penetration and redox-modulating effects in the central nervous system. As a direct precursor of GSH, NAC replenishes intracellular cysteine pools to enhance GSH biosynthesis and bolster cellular antioxidant defenses (235). In AD, NAC elevates GSH levels to sustain GPX4 activity, thereby reducing lipid peroxidation accumulation and inhibiting key ferroptosis pathways for neuroprotection (188).

Vitamin K compounds (phylloquinone, menaquinone-4/MK4, menadione) exhibit broad-spectrum ferroptosis suppression via a non-canonical FSP1-mediated pathway, identifying them as critical substrates for an endogenous anti-ferroptotic system independent of GSH/GPX4 (86). Nonetheless, natural vitamin K forms (e.g., phylloquinone) achieve brain concentrations only ~2% of plasma levels, substantially below the threshold required for neuronal ferroptosis inhibition. Current clinical advancement strategies include structural engineering of vitamin K analogs (e.g., C11-alkyl chain-modified MK4-C11) to enhance brain bioavailability and adeno-associated virus (AAV)-mediated FSP1 gene delivery (NCT05543659) to restore vitamin K reduction capacity, driving the transformation of vitamin K from a fundamental nutrient into a clinically viable targeted ferroptosis therapeutic.

7.3 Free radical scavengers

7.3.1 Preclinical stage

Ferrostatin-1 (Fer-1), a canonical radical-trapping antioxidant (RTA), is a cornerstone of ferroptosis research with robust preclinical efficacy (236). As a first-generation ferroptosis inhibitor, its core mechanism involves direct interception of lipid radicals to terminate peroxidation chain reactions: its arylamine group (-NH-) donates hydrogen atoms (H•) to reduce lipid peroxyl radicals (LOO• → LOOH), a mechanism analogous to vitamin E but with superior ferroptosis-inhibitory efficacy (237). Additionally, Fer-1 reduces lipid peroxidation by diminishing Fe²⁺-mediated oxygen radical levels, mitigating oxidation of polyunsaturated fatty acids (PUFAs) in cellular membranes to preserve integrity. Operating independently of GPX4 or FSP1, Fer-1 exhibits efficacy across diverse ferroptosis models (e.g., RSL3- or erastin-induced ferroptosis). However, its clinical applicability is severely constrained by poor stability and susceptibility to oxidation, limiting its translational potential.

Ginkgolide B, a core bioactive component of Ginkgo biloba extract, demonstrates preclinical therapeutic potential in AD by ameliorating radical damage and inflammation, and exerting anti-ferroptotic effects via modulation of Nrf2-dependent pathways (238–240). Its neuroprotective mechanisms encompass suppression of PI3K/Akt and TLR4/NF-κB signaling, induction of heme oxygenase-1 (HO-1) expression, and regulation of anti-apoptotic/pro-apoptotic protein balance (241), suggesting it alleviates AD-associated cognitive impairment through ferroptosis inhibition (242). Despite these preclinical benefits, ginkgolide B’s clinical translation requires further validation of BBB penetration efficiency and long-term safety.

Edaravone (EDA), another radical scavenger, has recently shown preclinical potential for treating neurodegenerative diseases including AD through modulation of ferroptosis-related pathways (243, 244). Preclinical studies support its neuroprotective effects in AD models, though clinical validation remains pending (245).

7.3.2 Clinical stage

Vitamin E (α-tocopherol) is a clinically validated free radical scavenger with well-established ferroptosis-inhibitory effects: its chromanol phenolic hydroxyl group potently quenches lipid peroxyl radicals (LOO•) to terminate peroxidation chains. Clinical biochemistry studies reveal significantly reduced vitamin E levels in plasma, serum, and cerebrospinal fluid of AD patients, inversely correlating with disease severity. Randomized controlled trials confirm that daily vitamin E supplementation effectively slows cognitive decline in mild-to-moderate AD patients, supporting its role as a disease-modifying agent (246). Beyond vitamin E, nutritional interventions with ω-3 PUFAs have shown clinical relevance for AD prevention: long-term ω-3 PUFA intake in middle-aged adults lowers cerebrospinal 4-HNE levels and reduces preclinical AD risk, providing scientific rationale for nutrition-based primary prevention strategies targeting ferroptosis (247).

7.4 Synergistic intervention

7.4.1 Combination of Nrf2 activators and Aβ clearance

Nrf2 activators centered on sulforaphane are driving a paradigm shift in AD treatment from traditional single-pathway approaches toward a dual-track strategy targeting both pathological clearance and ferroptosis blockade. Nuclear-translocated Nrf2 directly downregulates BACE1 and its antisense RNA (BACE1-AS), suppressing Aβ generation; concurrently, it coordinately upregulates GPX4 expression, enhances GSH synthesis, and modulates iron metabolism proteins to effectively inhibit neuronal ferroptosis (248, 249). Natural compounds eriodictyol and ginkgolide B potentiate this effect: eriodictyol ameliorates amyloid pathology via vitamin D receptor (VDR)-mediated Nrf2/HO-1 signaling, while ginkgolide B reinforces the Nrf2/GPX4 axis to mitigate neuroinflammation-induced ferroptosis (242). Additionally, MG53 protein activates the Nrf2 pathway in senescent human umbilical cord mesenchymal stem cells (hUC-MSCs), significantly enhancing their capacity to clear Aβ deposits and suppress neuronal ferroptosis, thereby advancing sulforaphane-cell combination therapy (250).

Two hybrid compounds derived from natural products—7-O-cinnamoyl-paclitaxel and 7-O-feruloyl-paclitaxel—exhibit potent synergistic neuroprotection in HT22 cell injury models (251). In AD mice induced by intracerebral oligomeric Aβ25–35 peptide injection, both compounds individually alleviate neurotoxicity and improve short-term memory (validated by novel object recognition and Morris water maze tests), likely through Nrf2 pathway activation under oxidative stress. This upregulates downstream antioxidant enzymes (e.g., HO-1, NQO1) and maintains intracellular GSH levels, reducing ROS accumulation and enhancing neuronal resistance to Aβ toxicity (251).

Despite the promising preclinical therapeutic potential, clinical translation faces multiple challenges: sustained Nrf2 activation regulates over 200 target genes, posing oncogenic risks (e.g., pancreatic ductal hyperplasia); natural Nrf2 activators typically exhibit suboptimal blood-brain barrier penetration; and late-stage AD neuronal apoptosis substantially diminishes Nrf2 activation efficiency. Current research focuses on overcoming these limitations through nanotechnology-enabled brain-targeted delivery systems and real-time monitoring techniques, aiming to accelerate the clinical application of Nrf2-based combination therapies.

7.4.2 Combined treatment with metformin and alpha-lipoic acid

Lipoic acid, a potent antioxidant, activates the cytoprotective Nrf2 pathway. Metformin may suppress the key ferroptosis driver ACSL4 (which promotes toxic lipid biosynthesis) through AMPK pathway activation or reduce iron-dependent cellular damage by modulating iron metabolism-related proteins (e.g., downregulating transferrin receptor). Their combination theoretically offers a dual ferroptosis-inhibitory mechanism via concurrent Nrf2 activation and AMPK/ACSL4 suppression, particularly relevant in neurodegenerative contexts like AD.

Interim results from the NCT04886001 trial demonstrated clinical efficacy of the combination: it significantly improved cognitive function in early AD patients (assessed by ADAS-Cog13, with enhanced effects in APOE4-negative subgroups) and reduced CSF p-tau pathology compared with placebo, alongside an acceptable safety profile. However, the trial had limitations: it neither measured ferroptosis biomarkers (e.g., ACSL4/Ptgs2) nor included monotherapy control arms, thereby precluding validation of the putative anti-ferroptotic mechanism or synergistic superiority of the combination. This mechanistic hypothesis requires confirmation through dedicated studies.

7.4.3 Multi-target cocktail approach

Current therapeutic strategies for AD prioritize pharmacotherapy supplemented by rehabilitative training, as single-target or monotherapeutic approaches yield largely unsatisfactory outcomes, establishing multitarget combination therapies (“cocktail therapy”) as the emerging mainstream paradigm. This integrates multiple clinical mechanisms—including neuroprotection, targeted modulation, and risk factor intervention—to comprehensively address core AD pathologies: Aβ deposition, tau hyperphosphorylation, ferroptosis, and neuroinflammatory cross-talk.

The regimen emphasizes stage-specific interventions: early-stage management combines Aβ-clearing agents (e.g., aducanumab) with ferroptosis inhibitors (e.g., sulforaphane via Nrf2/GPX4 activation) to reduce Aβ plaques and counteract oxidative stress/lipid peroxidation; mid-stage progression incorporates tau-targeting and anti-inflammatory compounds such as phillyrin A to mitigate chronic neuroinflammation (252). late-stage maintenance therapy introduces human umbilical cord mesenchymal stem cell (hUC-MSC) transplantation to promote neuronal regeneration.

To ensure effective and stable intracerebral drug concentrations, continuous optimization of delivery systems is pursued, exemplified by hyperpermeable selenium nanoparticles coupled with focused ultrasound for precise antibody targeting. Focused ultrasound-microbubble technology represents a promising non-invasive delivery approach, offering minimal invasiveness and enhanced safety for CNS drug administration. Further advancing this field, the clinical trial NCT05218903 is evaluating subcutaneous versus intravenous delivery of lecanemab in early Alzheimer’s disease. The study assesses the safety, tolerability, and bioactivity of the subcutaneous formulation; its primary goal is to determine whether this route maintains therapeutic efficacy while offering greater convenience. Results are expected in 2025.

7.5 Critical discussion of translational challenges

The translation of ferroptosis-targeting agents for AD faces multiple interconnected challenges, with BBB penetration, off-target effects, long-term safety, and perturbations of iron metabolism and immune function being the most prominent. BBB penetration remains a primary bottleneck: natural compounds (curcumin, phillyrin A) and some synthetic agents (DFO) exhibit poor brain bioavailability, necessitating delivery system modification (e.g., nanoparticle conjugates) or structural optimization (e.g., vitamin K analogs). While agents like DFP and NAC demonstrate favorable BBB penetration, their systemic effects on iron metabolism raise concerns: iron chelators can induce unintended iron deficiency in peripheral tissues, while antioxidants may disrupt physiological redox balance, highlighting the need for brain-targeted delivery to minimize off-target effects.

Long-term safety profiles are another critical consideration. Neutropenia associated with iron chelation therapy and potential hepatic/renal toxicity underscore the importance of continuous monitoring of organ function during clinical application. For nutritional antioxidants (vitamin E, ω-3 PUFAs), long-term high-dose supplementation may carry risks (e.g., increased bleeding risk with vitamin E), requiring careful dose optimization. Additionally, the interplay between ferroptosis inhibition and immune function is poorly understood: iron is essential for immune cell activation, and systemic iron chelation could compromise immune surveillance, representing an understudied off-target effect.

Future translational efforts must prioritize strategies that enhance brain specificity (e.g., targeted delivery systems, BBB-penetrating analogs) while conducting comprehensive long-term safety assessments. Integrating multi-mechanistic agents (e.g., curcumin’s dual iron chelation and Aβ inhibition, CNB-001’s synergistic antioxidant and anti-inflammatory effects) may improve efficacy while reducing required doses, thereby minimizing off-target risks. Finally, rigorous clinical trials evaluating not only cognitive outcomes but also biomarkers of iron metabolism, lipid peroxidation, and immune function will be essential to validate the safety and efficacy of ferroptosis-targeting therapies for AD.

8 Limitations

In the context where AD research has encountered therapeutic bottlenecks with traditional “Aβ/tau” targets, the introduction of ferroptosis offers a novel and crucial perspective for understanding the disease. It not only molecularly links oxidative stress and iron dyshomeostasis with classical protein pathologies, forming an integrated pathogenic framework of “iron-Aβ/tau-neuronal death,” but also reveals an actionable cell death execution pathway. This provides substantial hope for developing disease-modifying therapies that go beyond mere protein clearance.

However, as this promising field transitions from basic discovery to clinical application, it faces a series of core challenges and limitations that must be addressed. Current evidence predominantly shows correlative phenomena such as iron accumulation, lipid peroxidation, and GPX4 downregulation. Yet, the precise spatiotemporal causal sequence among these three elements remains unconfirmed by longitudinal human studies. A contributory unanswered question is: is ferroptosis an early key driver of neurodegeneration, or a late-stage “executor” triggered by other pathologies?

Significant shortfalls also exist in clinical translation. While QSM-based MRI can non-invasively quantify brain iron, highly specific and sensitive fluid-based (blood/CSF) ferroptosis biomarkers are still lacking. Existing markers (e.g., 4-HNE, MDA) generally lack disease specificity, and their integrative analysis with classical AD biomarkers like Aβ and tau is insufficient. Regarding therapeutic strategies, interventions based on animal models (e.g., iron chelators, antioxidants) face a dual dilemma of target specificity and safety. Systemic drug administration struggles to precisely target affected brain regions and easily disrupts systemic iron homeostasis. Long-term inhibition of core pathways like GPX4 carries unknown risks, while targeting upstream regulators like Nrf2 harbors potential off-target effects due to their broad biological functions. Furthermore, mechanistic research heavily relies on transgenic AD mouse models (e.g., APP/PS1), which primarily model Aβ pathology. The similarity of their iron dysregulation and ferroptosis phenotypes to human AD remains questionable, limiting the translational power of the conclusions.

Ferroptosis does not occur in isolation; it is intricately interlinked with other core pathological processes in AD, including neuroinflammation and mitochondrial dysfunction. To advance this field, ferroptosis must be positioned within a broader systems biology framework of AD. Elucidating its precise mechanistic contribution and hierarchical significance within this complex pathogenic network is essential for achieving fundamental theoretical insights and enabling successful clinical translation.

9 Conclusion

AD is a neurodegenerative disorder characterized by neuronal loss and cognitive dysfunction, featuring hallmark pathological lesions including Aβ plaques and NFTs resulting from aberrant tau hyperphosphorylation. Although neuronal demise involves crosstalk among multiple cell death pathways, the contribution of ferroptosis has become increasingly evident. Ferroptosis—an iron-dependent regulated cell death distinct from apoptosis, necrosis, and autophagy—plays an important role in AD pathogenesis. Its core mechanisms encompass imbalance in iron homeostasis, enhanced lipid peroxidation, and GSH metabolic dysregulation, intersecting fundamentally with AD pathophysiology. Inhibiting ferroptosis via iron chelators, radical-trapping agents, and other interventions demonstrates significant improvements in neuronal survival and synaptic function across diverse preclinical models, establishing ferroptosis targeting as a promising novel therapeutic strategy for AD.

The current AD therapeutic landscape faces substantial challenges, with the lack of effective disease-modifying drugs underscoring the urgent need for preventive interventions. While healthy lifestyle modifications may partially mitigate age-related cognitive decline, precise molecular targeting remains indispensable. The efficacy of ferroptosis inhibitors in AD models reveals three key therapeutic development avenues: modulation of iron metabolism, suppression of lipid peroxidation, and restoration of GSH system functionality. Future research should prioritize elucidating dynamic iron transport mechanisms across the blood-brain barrier, validating combination therapies targeting synergistic ferroptosis regulators (e.g., Nrf2/GPX4/FSP1), and advancing preclinical findings toward biomarker identification and precision intervention protocols. In summary, as a critical component in AD pathology, mechanistic investigation and therapeutic exploration of ferroptosis hold significant importance, necessitating further multidimensional and interdisciplinary research to comprehensively understand its relationship with AD and drive innovative treatment development.

Author contributions

YQ: Writing – original draft. HL: Writing – original draft. MZ: Writing – original draft. ML: Writing – original draft. BH: Writing – original draft. KW: Writing – original draft. XH: Writing – original draft. SZ: Writing – original draft. ZH: Writing – original draft. HF: Writing – original draft, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by Shanxi Health Committee Foundation Project (2024057) and Fundamental Research Program of Shanxi Province (202403021222432).

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, et al. Alzheimer’s disease. Lancet. (2021) 397:1577–90. doi: 10.1016/s0140-6736(20)32205-4

PubMed Abstract | Crossref Full Text | Google Scholar

2. Jash K, Gondaliya P, Kirave P, Kulkarni B, Sunkaria A, and Kalia K. Cognitive dysfunction: A growing link between diabetes and alzheimer’s disease. Drug Dev Res. (2020) 81:144–64. doi: 10.1002/ddr.21579

PubMed Abstract | Crossref Full Text | Google Scholar

3. Graff-Radford J, Yong KXX, Apostolova LG, Bouwman FH, Carrillo M, Dickerson BC, et al. New insights into atypical alzheimer’s disease in the era of biomarkers. Lancet Neurol. (2021) 20:222–34. doi: 10.1016/s1474-4422(20)30440-3

PubMed Abstract | Crossref Full Text | Google Scholar

4. Perry G, Friedman R, Shaw G, and Chau V. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of alzheimer disease brains. Proc Natl Acad Sci U.S.A. (1987) 84:3033–6. doi: 10.1073/pnas.84.9.3033

PubMed Abstract | Crossref Full Text | Google Scholar

5. Vallet PG, Guntern R, Hof PR, Golaz J, Delacourte A, Robakis NK, et al. A comparative study of histological and immunohistochemical methods for neurofibrillary tangles and senile plaques in alzheimer’s disease. Acta Neuropathol. (1992) 83:170–8. doi: 10.1007/bf00308476

PubMed Abstract | Crossref Full Text | Google Scholar

6. Knopman DS, Jones DT, and Greicius MD. Failure to demonstrate efficacy of aducanumab: an analysis of the emerge and engage trials as reported by biogen, december 2019. Alzheimers Dement. (2021) 17:696–701. doi: 10.1002/alz.12213

PubMed Abstract | Crossref Full Text | Google Scholar

7. McDade E, Voytyuk I, Aisen P, Bateman RJ, Carrillo MC, De Strooper B, et al. The case for low-level bace1 inhibition for the prevention of alzheimer disease. Nat Rev Neurol. (2021) 17:703–14. doi: 10.1038/s41582-021-00545-1

PubMed Abstract | Crossref Full Text | Google Scholar

8. van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early alzheimer’s disease. N Engl J Med. (2023) 388:9–21. doi: 10.1056/NEJMoa2212948

PubMed Abstract | Crossref Full Text | Google Scholar

9. Serrano-Pozo A, Das S, and Hyman BT. Apoe and alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol. (2021) 20:68–80. doi: 10.1016/s1474-4422(20)30412-9

PubMed Abstract | Crossref Full Text | Google Scholar

10. Ward RJ, Zucca FA, Duyn JH, Crichton RR, and Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. (2014) 13:1045–60. doi: 10.1016/s1474-4422(14)70117-6

PubMed Abstract | Crossref Full Text | Google Scholar

11. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. (2012) 149:1060–72. doi: 10.1016/j.cell.2012.03.042

PubMed Abstract | Crossref Full Text | Google Scholar

12. Honda K, Smith MA, Zhu X, Baus D, Merrick WC, Tartakoff AM, et al. Ribosomal rna in alzheimer disease is oxidized by bound redox-active iron. J Biol Chem. (2005) 280:20978–86. doi: 10.1074/jbc.M500526200

PubMed Abstract | Crossref Full Text | Google Scholar

13. Alim I, Caulfield JT, Chen Y, Swarup V, Geschwind DH, Ivanova E, et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell. (2019) 177:1262–79.e25. doi: 10.1016/j.cell.2019.03.032

PubMed Abstract | Crossref Full Text | Google Scholar

14. Wu JR, Tuo QZ, and Lei P. Ferroptosis, a recent defined form of critical cell death in neurological disorders. J Mol Neurosci. (2018) 66:197–206. doi: 10.1007/s12031-018-1155-6

PubMed Abstract | Crossref Full Text | Google Scholar

15. Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, et al. Ferroptosis: past, present and future. Cell Death Dis. (2020) 11:88. doi: 10.1038/s41419-020-2298-2

PubMed Abstract | Crossref Full Text | Google Scholar

16. Vitalakumar D, Sharma A, and Flora SJS. Ferroptosis: A potential therapeutic target for neurodegenerative diseases. J Biochem Mol Toxicol. (2021) 35:e22830. doi: 10.1002/jbt.22830

PubMed Abstract | Crossref Full Text | Google Scholar

17. Ashraf A, Jeandriens J, Parkes HG, and So PW. Iron dyshomeostasis, lipid peroxidation and perturbed expression of cystine/glutamate antiporter in alzheimer’s disease: evidence of ferroptosis. Redox Biol. (2020) 32:101494. doi: 10.1016/j.redox.2020.101494

PubMed Abstract | Crossref Full Text | Google Scholar

18. Ayton S, Wang Y, Diouf I, Schneider JA, Brockman J, Morris MC, et al. Brain iron is associated with accelerated cognitive decline in people with alzheimer pathology. Mol Psychiatry. (2020) 25:2932–41. doi: 10.1038/s41380-019-0375-7

PubMed Abstract | Crossref Full Text | Google Scholar

19. Hambright WS, Fonseca RS, Chen L, Na R, and Ran Q. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol. (2017) 12:8–17. doi: 10.1016/j.redox.2017.01.021

PubMed Abstract | Crossref Full Text | Google Scholar

20. Goedert M. Oskar fischer and the study of dementia. Brain. (2009) 132:1102–11. doi: 10.1093/brain/awn256

PubMed Abstract | Crossref Full Text | Google Scholar

21. Blennow K and Zetterberg H. Biomarkers for alzheimer’s disease: current status and prospects for the future. J Intern Med. (2018) 284:643–63. doi: 10.1111/joim.12816

PubMed Abstract | Crossref Full Text | Google Scholar

22. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at clu and picalm associated with alzheimer’s disease. Nat Genet. (2009) 41:1088–93. doi: 10.1038/ng.440

PubMed Abstract | Crossref Full Text | Google Scholar

23. Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, and Gauthier S. Apolipoprotein E polymorphism and alzheimer’s disease. Lancet. (1993) 342:697–9. doi: 10.1016/0140-6736(93)91705-q

PubMed Abstract | Crossref Full Text | Google Scholar

24. Morris GP, Clark IA, and Vissel B. Inconsistencies and controversies surrounding the amyloid hypothesis of alzheimer’s disease. Acta Neuropathol Commun. (2014) 2:135. doi: 10.1186/s40478-014-0135-5

PubMed Abstract | Crossref Full Text | Google Scholar

25. Irizarry MC, McNamara M, Fedorchak K, Hsiao K, and Hyman BT. Appsw transgenic mice develop age-related a beta deposits and neuropil abnormalities, but no neuronal loss in ca1. J Neuropathol Exp Neurol. (1997) 56:965–73. doi: 10.1097/00005072-199709000-00002

PubMed Abstract | Crossref Full Text | Google Scholar

26. Plowey ED, Bussiere T, Rajagovindan R, Sebalusky J, Hamann S, von Hehn C, et al. Alzheimer disease neuropathology in a patient previously treated with aducanumab. Acta Neuropathol. (2022) 144:143–53. doi: 10.1007/s00401-022-02433-4

PubMed Abstract | Crossref Full Text | Google Scholar

27. Shi M, Chu F, Zhu F, and Zhu J. Impact of anti-amyloid-B Monoclonal antibodies on the pathology and clinical profile of alzheimer’s disease: A focus on aducanumab and lecanemab. Front Aging Neurosci. (2022) 14:870517. doi: 10.3389/fnagi.2022.870517

PubMed Abstract | Crossref Full Text | Google Scholar

28. Coby AJ, Picardal F, Shelobolina E, Xu H, and Roden EE. Repeated anaerobic microbial redox cycling of iron. Appl Environ Microbiol. (2011) 77:6036–42. doi: 10.1128/aem.00276-11

PubMed Abstract | Crossref Full Text | Google Scholar

29. Nemeth E and Ganz T. Hepcidin-ferroportin interaction controls systemic iron homeostasis. Int J Mol Sci. (2021) 22:6493. doi: 10.3390/ijms22126493

PubMed Abstract | Crossref Full Text | Google Scholar

30. Jenkins NL, James SA, Salim A, Sumardy F, Speed TP, Conrad M, et al. Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging caenorhabditis elegans. eLife. (2020) 9:e56580. doi: 10.7554/eLife.56580

PubMed Abstract | Crossref Full Text | Google Scholar

31. Zhao T, Guo X, and Sun Y. Iron accumulation and lipid peroxidation in the aging retina: implication of ferroptosis in age-related macular degeneration. Aging Dis. (2021) 12:529–51. doi: 10.14336/ad.2020.0912

PubMed Abstract | Crossref Full Text | Google Scholar

32. Johnsen KB, Burkhart A, Thomsen LB, Andresen TL, and Moos T. Targeting the transferrin receptor for brain drug delivery. Prog Neurobiol. (2019) 181:101665. doi: 10.1016/j.pneurobio.2019.101665

PubMed Abstract | Crossref Full Text | Google Scholar

33. Gammella E, Buratti P, Cairo G, and Recalcati S. The transferrin receptor: the cellular iron gate. Metallomics. (2017) 9:1367–75. doi: 10.1039/c7mt00143f

PubMed Abstract | Crossref Full Text | Google Scholar

34. Pardridge WM, Eisenberg J, and Yang J. Human blood-brain barrier transferrin receptor. Metabolism. (1987) 36:892–5. doi: 10.1016/0026-0495(87)90099-0

PubMed Abstract | Crossref Full Text | Google Scholar

35. Knutson MD. Non-transferrin-bound iron transporters. Free Radic Biol Med. (2019) 133:101–11. doi: 10.1016/j.freeradbiomed.2018.10.413

PubMed Abstract | Crossref Full Text | Google Scholar

36. Hect JL, Daugherty AM, Hermez KM, and Thomason ME. Developmental variation in regional brain iron and its relation to cognitive functions in childhood. Dev Cognit Neurosci. (2018) 34:18–26. doi: 10.1016/j.dcn.2018.05.004

PubMed Abstract | Crossref Full Text | Google Scholar

37. Andreini C, Putignano V, Rosato A, and Banci L. The human iron-proteome. Metallomics. (2018) 10:1223–31. doi: 10.1039/c8mt00146d

PubMed Abstract | Crossref Full Text | Google Scholar

38. Beard JL and Connor JR. Iron status and neural functioning. Annu Rev Nutr. (2003) 23:41–58. doi: 10.1146/annurev.nutr.23.020102.075739

PubMed Abstract | Crossref Full Text | Google Scholar

39. Masaldan S, Bush AI, Devos D, Rolland AS, and Moreau C. Striking while the iron is hot: iron metabolism and ferroptosis in neurodegeneration. Free Radic Biol Med. (2019) 133:221–33. doi: 10.1016/j.freeradbiomed.2018.09.033

PubMed Abstract | Crossref Full Text | Google Scholar

40. Smith MA, Harris PL, Sayre LM, and Perry G. Iron accumulation in alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U.S.A. (1997) 94:9866–8. doi: 10.1073/pnas.94.18.9866

PubMed Abstract | Crossref Full Text | Google Scholar

41. Mao J, McKean DM, Warrier S, Corbin JG, Niswander L, and Zohn IE. The iron exporter ferroportin 1 is essential for development of the mouse embryo, forebrain patterning and neural tube closure. Development. (2010) 137:3079–88. doi: 10.1242/dev.048744

PubMed Abstract | Crossref Full Text | Google Scholar

42. Xian-hui D, Wei-juan G, Tie-mei S, Hong-lin X, Jiang-tao B, Jing-yi Z, et al. Age-related changes of brain iron load changes in the frontal cortex in appswe/ps1δe9 transgenic mouse model of alzheimer’s disease. J Trace Elem Med Biol. (2015) 30:118–23. doi: 10.1016/j.jtemb.2014.11.009

PubMed Abstract | Crossref Full Text | Google Scholar

43. Belaidi AA, Gunn AP, Wong BX, Ayton S, Appukuttan AT, Roberts BR, et al. Marked age-related changes in brain iron homeostasis in amyloid protein precursor knockout mice. Neurotherapeutics. (2018) 15:1055–62. doi: 10.1007/s13311-018-0656-x

PubMed Abstract | Crossref Full Text | Google Scholar

44. Bao WD, Pang P, Zhou XT, Hu F, Xiong W, Chen K, et al. Loss of ferroportin induces memory impairment by promoting ferroptosis in alzheimer’s disease. Cell Death Differ. (2021) 28:1548–62. doi: 10.1038/s41418-020-00685-9

PubMed Abstract | Crossref Full Text | Google Scholar

45. Ou M, Jiang Y, Ji Y, Zhou Q, Du Z, Zhu H, et al. Role and mechanism of ferroptosis in neurological diseases. Mol Metab. (2022) 61:101502. doi: 10.1016/j.molmet.2022.101502

PubMed Abstract | Crossref Full Text | Google Scholar

46. Zhu Z, Wang Y, Deng Z, Lei P, Liu Q, Guo J, et al. The Hemerocallis Citrina Extracts Ameliorate Radiation-Induced Ferroptosis in Lo2 Cells through the Nrf2-Xct/Gpx4 Pathway. J Acupuncture Herbal Med. (2024) 4:513–24. doi: 10.1097/HM9.0000000000000120

Crossref Full Text | Google Scholar

47. Yuan H, Li X, Zhang X, Kang R, and Tang D. Identification of acsl4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. (2016) 478:1338–43. doi: 10.1016/j.bbrc.2016.08.124

PubMed Abstract | Crossref Full Text | Google Scholar

48. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. Acsl4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. (2017) 13:91–8. doi: 10.1038/nchembio.2239

PubMed Abstract | Crossref Full Text | Google Scholar

49. Snaebjornsson MT, Janaki-Raman S, and Schulze A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell Metab. (2020) 31:62–76. doi: 10.1016/j.cmet.2019.11.010

PubMed Abstract | Crossref Full Text | Google Scholar

50. Kagan JC. Lipopolysaccharide detection across the kingdoms of life. Trends Immunol. (2017) 38:696–704. doi: 10.1016/j.it.2017.05.001

PubMed Abstract | Crossref Full Text | Google Scholar

51. Zhang HL, Hu BX, Li ZL, Du T, Shan JL, Ye ZP, et al. Pkcβii phosphorylates acsl4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol. (2022) 24:88–98. doi: 10.1038/s41556-021-00818-3

PubMed Abstract | Crossref Full Text | Google Scholar

52. Tcw J, Qian L, Pipalia NH, Chao MJ, Liang SA, Shi Y, et al. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia. Cell. (2022) 185:2213–33.e25. doi: 10.1016/j.cell.2022.05.017

PubMed Abstract | Crossref Full Text | Google Scholar

53. Martens YA, Zhao N, Liu CC, Kanekiyo T, Yang AJ, Goate AM, et al. Apoe cascade hypothesis in the pathogenesis of alzheimer’s disease and related dementias. Neuron. (2022) 110:1304–17. doi: 10.1016/j.neuron.2022.03.004

PubMed Abstract | Crossref Full Text | Google Scholar

54. Thorwald MA, Godoy-Lugo JA, Garcia G, Silva J, Kim M, Christensen A, et al. Iron-associated lipid peroxidation in alzheimer’s disease is increased in lipid rafts with decreased ferroptosis suppressors, tested by chelation in mice. Alzheimers Dement. (2025) 21:e14541. doi: 10.1002/alz.14541

PubMed Abstract | Crossref Full Text | Google Scholar

55. Jaganjac M, Milkovic L, Gegotek A, Cindric M, Zarkovic K, Skrzydlewska E, et al. The relevance of pathophysiological alterations in redox signaling of 4-hydroxynonenal for pharmacological therapies of major stress-associated diseases. Free Radic Biol Med. (2020) 157:128–53. doi: 10.1016/j.freeradbiomed.2019.11.023

PubMed Abstract | Crossref Full Text | Google Scholar

56. Keller JN, Mark RJ, Bruce AJ, Blanc E, Rothstein JD, Uchida K, et al. 4-hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes. Neuroscience. (1997) 80:685–96. doi: 10.1016/s0306-4522(97)00065-1

PubMed Abstract | Crossref Full Text | Google Scholar

57. Feng H and Stockwell BR. Unsolved mysteries: how does lipid peroxidation cause ferroptosis? PloS Biol. (2018) 16:e2006203. doi: 10.1371/journal.pbio.2006203

PubMed Abstract | Crossref Full Text | Google Scholar

58. Siegel SJ, Bieschke J, Powers ET, and Kelly JW. The oxidative stress metabolite 4-hydroxynonenal promotes alzheimer protofibril formation. Biochemistry. (2007) 46:1503–10. doi: 10.1021/bi061853s

PubMed Abstract | Crossref Full Text | Google Scholar

59. Li FJ, Long HZ, Zhou ZW, Luo HY, Xu SG, and Gao LC. System X(C) (-)/gsh/gpx4 axis: an important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy. Front Pharmacol. (2022) 13:910292. doi: 10.3389/fphar.2022.910292

PubMed Abstract | Crossref Full Text | Google Scholar

60. Wu J, Wang Y, Jiang R, Xue R, Yin X, Wu M, et al. Ferroptosis in liver disease: new insights into disease mechanisms. Cell Death Discov. (2021) 7:276. doi: 10.1038/s41420-021-00660-4

PubMed Abstract | Crossref Full Text | Google Scholar

61. Lewerenz J and Maher P. Control of redox state and redox signaling by neural antioxidant systems. Antioxid Redox Signal. (2011) 14:1449–65. doi: 10.1089/ars.2010.3600

PubMed Abstract | Crossref Full Text | Google Scholar

62. Cao JY and Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. (2016) 73:2195–209. doi: 10.1007/s00018-016-2194-1

PubMed Abstract | Crossref Full Text | Google Scholar

63. Dodson M, Castro-Portuguez R, and Zhang DD. Nrf2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. (2019) 23:101107. doi: 10.1016/j.redox.2019.101107

PubMed Abstract | Crossref Full Text | Google Scholar

64. Wei S, Yu Z, Shi R, An L, Zhang Q, Zhang Q, et al. Gpx4 suppresses ferroptosis to promote Malignant progression of endometrial carcinoma via transcriptional activation by elk1. BMC Cancer. (2022) 22:881. doi: 10.1186/s12885-022-09986-3

PubMed Abstract | Crossref Full Text | Google Scholar

65. Xie Y, Kang R, Klionsky DJ, and Tang D. Gpx4 in cell death, autophagy, and disease. Autophagy. (2023) 19:2621–38. doi: 10.1080/15548627.2023.2218764

PubMed Abstract | Crossref Full Text | Google Scholar

66. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by gpx4. Cell. (2014) 156:317–31. doi: 10.1016/j.cell.2013.12.010

PubMed Abstract | Crossref Full Text | Google Scholar

67. Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, et al. Selenium utilization by gpx4 is required to prevent hydroperoxide-induced ferroptosis. Cell. (2018) 172:409–22.e21. doi: 10.1016/j.cell.2017.11.048

PubMed Abstract | Crossref Full Text | Google Scholar

68. Gansemer ER, McCommis KS, Martino M, King-McAlpin AQ, Potthoff MJ, Finck BN, et al. Nadph and glutathione redox link tca cycle activity to endoplasmic reticulum homeostasis. iScience. (2020) 23:101116. doi: 10.1016/j.isci.2020.101116

PubMed Abstract | Crossref Full Text | Google Scholar

69. Suzuki T, Motohashi H, and Yamamoto M. Toward clinical application of the keap1-nrf2 pathway. Trends Pharmacol Sci. (2013) 34:340–6. doi: 10.1016/j.tips.2013.04.005

PubMed Abstract | Crossref Full Text | Google Scholar

70. Sivandzade F, Bhalerao A, and Cucullo L. Cerebrovascular and neurological disorders: protective role of nrf2. Int J Mol Sci. (2019) 20:3433. doi: 10.3390/ijms20143433

PubMed Abstract | Crossref Full Text | Google Scholar

71. Nioi P, Nguyen T, Sherratt PJ, and Pickett CB. The carboxy-terminal neh3 domain of nrf2 is required for transcriptional activation. Mol Cell Biol. (2005) 25:10895–906. doi: 10.1128/mcb.25.24.10895-10906.2005

PubMed Abstract | Crossref Full Text | Google Scholar

72. Wang H, Liu K, Geng M, Gao P, Wu X, Hai Y, et al. Rxrα Inhibits the nrf2-are signaling pathway through a direct interaction with the neh7 domain of nrf2. Cancer Res. (2013) 73:3097–108. doi: 10.1158/0008-5472.Can-12-3386

PubMed Abstract | Crossref Full Text | Google Scholar

73. Chowdhry S, Zhang Y, McMahon M, Sutherland C, Cuadrado A, and Hayes JD. Nrf2 is controlled by two distinct B-trcp recognition motifs in its neh6 domain, one of which can be modulated by gsk-3 activity. Oncogene. (2013) 32:3765–81. doi: 10.1038/onc.2012.388

PubMed Abstract | Crossref Full Text | Google Scholar

74. Miseta A and Csutora P. Relationship between the occurrence of cysteine in proteins and the complexity of organisms. Mol Biol Evol. (2000) 17:1232–9. doi: 10.1093/oxfordjournals.molbev.a026406

PubMed Abstract | Crossref Full Text | Google Scholar

75. Prestera T, Holtzclaw WD, Zhang Y, and Talalay P. Chemical and molecular regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci U.S.A. (1993) 90:2965–9. doi: 10.1073/pnas.90.7.2965

PubMed Abstract | Crossref Full Text | Google Scholar

76. Holland R, Hawkins AE, Eggler AL, Mesecar AD, Fabris D, and Fishbein JC. Prospective type 1 and type 2 disulfides of keap1 protein. Chem Res Toxicol. (2008) 21:2051–60. doi: 10.1021/tx800226m

PubMed Abstract | Crossref Full Text | Google Scholar

77. Motohashi H, Katsuoka F, Engel JD, and Yamamoto M. Small maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the keap1-nrf2 regulatory pathway. Proc Natl Acad Sci U.S.A. (2004) 101:6379–84. doi: 10.1073/pnas.0305902101

PubMed Abstract | Crossref Full Text | Google Scholar

78. Hirotsu Y, Katsuoka F, Funayama R, Nagashima T, Nishida Y, Nakayama K, et al. Nrf2-mafg heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res. (2012) 40:10228–39. doi: 10.1093/nar/gks827

PubMed Abstract | Crossref Full Text | Google Scholar

79. Yang R, Gao W, Wang Z, Jian H, Peng L, Yu X, et al. Polyphyllin I induced ferroptosis to suppress the progression of hepatocellular carcinoma through activation of the mitochondrial dysfunction via nrf2/ho-1/gpx4 axis. Phytomedicine. (2024) 122:155135. doi: 10.1016/j.phymed.2023.155135

PubMed Abstract | Crossref Full Text | Google Scholar

80. Chen X, Yu C, Kang R, and Tang D. Iron metabolism in ferroptosis. Front Cell Dev Biol. (2020) 8:590226. doi: 10.3389/fcell.2020.590226

PubMed Abstract | Crossref Full Text | Google Scholar

81. Chang CF, Cho S, and Wang J. (-)-epicatechin protects hemorrhagic brain via synergistic nrf2 pathways. Ann Clin Transl Neurol. (2014) 1:258–71. doi: 10.1002/acn3.54

PubMed Abstract | Crossref Full Text | Google Scholar

82. Hancock R, Bertrand HC, Tsujita T, Naz S, El-Bakry A, Laoruchupong J, et al. Peptide inhibitors of the keap1-nrf2 protein-protein interaction. Free Radic Biol Med. (2012) 52:444–51. doi: 10.1016/j.freeradbiomed.2011.10.486

PubMed Abstract | Crossref Full Text | Google Scholar

83. Jain A, Lamark T, Sjøttem E, Larsen KB, Awuh JA, Øvervatn A, et al. P62/sqstm1 is a target gene for transcription factor nrf2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem. (2010) 285:22576–91. doi: 10.1074/jbc.M110.118976

PubMed Abstract | Crossref Full Text | Google Scholar

84. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The coq oxidoreductase fsp1 acts parallel to gpx4 to inhibit ferroptosis. Nature. (2019) 575:688–92. doi: 10.1038/s41586-019-1705-2

PubMed Abstract | Crossref Full Text | Google Scholar

85. Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. Fsp1 is a glutathione-independent ferroptosis suppressor. Nature. (2019) 575:693–8. doi: 10.1038/s41586-019-1707-0

PubMed Abstract | Crossref Full Text | Google Scholar

86. Mishima E, Ito J, Wu Z, Nakamura T, Wahida A, Doll S, et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature. (2022) 608:778–83. doi: 10.1038/s41586-022-05022-3

PubMed Abstract | Crossref Full Text | Google Scholar

87. Nioi P and Hayes JD. Contribution of nad(P)H:Quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors. Mutat Res. (2004) 555:149–71. doi: 10.1016/j.mrfmmm.2004.05.023

PubMed Abstract | Crossref Full Text | Google Scholar

88. Chen X, Kang R, Kroemer G, and Tang D. Organelle-specific regulation of ferroptosis. Cell Death Differ. (2021) 28:2843–56. doi: 10.1038/s41418-021-00859-z

PubMed Abstract | Crossref Full Text | Google Scholar

89. Cotticelli MG, Xia S, Lin D, Lee T, Terrab L, Wipf P, et al. Ferroptosis as a novel therapeutic target for friedreich’s ataxia. J Pharmacol Exp Ther. (2019) 369:47–54. doi: 10.1124/jpet.118.252759

PubMed Abstract | Crossref Full Text | Google Scholar

90. Glover HL, Schreiner A, Dewson G, and Tait SWG. Mitochondria and cell death. Nat Cell Biol. (2024) 26:1434–46. doi: 10.1038/s41556-024-01429-4

PubMed Abstract | Crossref Full Text | Google Scholar

91. Liu Y, Lu S, Wu LL, Yang L, Yang L, and Wang J. The diversified role of mitochondria in ferroptosis in cancer. Cell Death Dis. (2023) 14:519. doi: 10.1038/s41419-023-06045-y

PubMed Abstract | Crossref Full Text | Google Scholar

92. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. (2009) 417:1–13. doi: 10.1042/bj20081386

PubMed Abstract | Crossref Full Text | Google Scholar

93. Martínez-Reyes I and Chandel NS. Mitochondrial tca cycle metabolites control physiology and disease. Nat Commun. (2020) 11:102. doi: 10.1038/s41467-019-13668-3

PubMed Abstract | Crossref Full Text | Google Scholar

94. Liu Z and Butow RA. Mitochondrial retrograde signaling. Annu Rev Genet. (2006) 40:159–85. doi: 10.1146/annurev.genet.40.110405.090613

PubMed Abstract | Crossref Full Text | Google Scholar

95. Peña FJ, Ortiz-Rodríguez JM, Gaitskell-Phillips GL, Gil MC, Ortega-Ferrusola C, and Martín-Cano FE. An integrated overview on the regulation of sperm metabolism (Glycolysis-krebs cycle-oxidative phosphorylation). Anim Reprod Sci. (2022) 246:106805. doi: 10.1016/j.anireprosci.2021.106805

PubMed Abstract | Crossref Full Text | Google Scholar

96. Ma J, Yuan H, Zhang J, Sun X, Yi L, Li W, et al. An ultrasound-activated nanoplatform remodels tumor microenvironment through diverse cell death induction for improved immunotherapy. J Controlled release: Off J Controlled Release Soc. (2024) 370:501–15. doi: 10.1016/j.jconrel.2024.05.001

PubMed Abstract | Crossref Full Text | Google Scholar

97. Yu M, Huo D, Yu K, Zhou K, Xu F, Meng Q, et al. Crosstalk of different cell-death patterns predicts prognosis and drug sensitivity in glioma. Comput Biol Med. (2024) 175:108532. doi: 10.1016/j.compbiomed.2024.108532

PubMed Abstract | Crossref Full Text | Google Scholar

98. Li W, Shi J, Yu Z, Garcia-Gabilondo M, Held A, Huang L, et al. Slc22a17 as a cell death-linked regulator of tight junctions in cerebral ischemia. Stroke. (2024) 55:1650–9. doi: 10.1161/strokeaha.124.046736

PubMed Abstract | Crossref Full Text | Google Scholar

99. Li Y, Deng X, Hu Q, Chen Y, Zhang W, Qin X, et al. Paeonia lactiflora pall. Ameliorates acetaminophen-induced oxidative stress and apoptosis via inhibiting the pkc-erk pathway. J ethnopharmacology. (2024) 329:118107. doi: 10.1016/j.jep.2024.118107

PubMed Abstract | Crossref Full Text | Google Scholar

100. Mou Y, Wang J, Wu J, He D, Zhang C, Duan C, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. (2019) 12:34. doi: 10.1186/s13045-019-0720-y

PubMed Abstract | Crossref Full Text | Google Scholar

101. Zheng DW, Lei Q, Zhu JY, Fan JX, Li CX, Li C, et al. Switching apoptosis to ferroptosis: metal-organic network for high-efficiency anticancer therapy. Nano Lett. (2017) 17:284–91. doi: 10.1021/acs.nanolett.6b04060

PubMed Abstract | Crossref Full Text | Google Scholar

102. Huang L, Zhang L, Zhang Z, Tan F, Ma Y, Zeng X, et al. Loss of nephric augmenter of liver regeneration facilitates acute kidney injury via acsl4-mediated ferroptosis. J Cell Mol Med. (2024) 28:e18076. doi: 10.1111/jcmm.18076

PubMed Abstract | Crossref Full Text | Google Scholar

103. López-Gil JC, García-Silva S, Ruiz-Cañas L, Navarro D, Palencia-Campos A, Giráldez-Trujillo A, et al. The peptidoglycan recognition protein 1 confers immune evasive properties on pancreatic cancer stem cells. Gut. (2024) 73:1489–508. doi: 10.1136/gutjnl-2023-330995

PubMed Abstract | Crossref Full Text | Google Scholar

104. Müller T, Dewitz C, Schmitz J, Schröder AS, Bräsen JH, Stockwell BR, et al. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell Mol Life Sci. (2017) 74:3631–45. doi: 10.1007/s00018-017-2547-4

PubMed Abstract | Crossref Full Text | Google Scholar

105. Ma L, Chen C, Zhao C, Li T, Ma L, Jiang J, et al. Targeting carnitine palmitoyl transferase 1a (Cpt1a) induces ferroptosis and synergizes with immunotherapy in lung cancer. Signal transduction targeted Ther. (2024) 9:64. doi: 10.1038/s41392-024-01772-w

PubMed Abstract | Crossref Full Text | Google Scholar

106. Chen J, Jin Z, Zhang S, Zhang X, Li P, Yang H, et al. Arsenic trioxide elicits prophylactic and therapeutic immune responses against solid tumors by inducing necroptosis and ferroptosis. Cell Mol Immunol. (2023) 20:51–64. doi: 10.1038/s41423-022-00956-0

PubMed Abstract | Crossref Full Text | Google Scholar

107. Zhang Y, Liu P, Yang S, Lan J, Xu H, Jiang H, et al. Nogo-B promotes endoplasmic reticulum stress-mediated autophagy in endothelial cells of diabetic nephropathy. Antioxid Redox Signal. (2024) 41:706–22. doi: 10.1089/ars.2023.0490

PubMed Abstract | Crossref Full Text | Google Scholar

108. Li M, Lei P, Shuang S, Dong C, and Zhang L. Visualization of polarity changes in endoplasmic reticulum (Er) autophagy and rheumatoid arthritis mice with near-infrared er-targeted fluorescent probe. Talanta. (2024) 275:126141. doi: 10.1016/j.talanta.2024.126141

PubMed Abstract | Crossref Full Text | Google Scholar

109. Mancias JD, Wang X, Gygi SP, Harper JW, and Kimmelman AC. Quantitative proteomics identifies ncoa4 as the cargo receptor mediating ferritinophagy. Nature. (2014) 509:105–9. doi: 10.1038/nature13148

PubMed Abstract | Crossref Full Text | Google Scholar

110. Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy. (2016) 12:1425–8. doi: 10.1080/15548627.2016.1187366

PubMed Abstract | Crossref Full Text | Google Scholar

111. Yan N and Zhang J. Iron metabolism, ferroptosis, and the links with alzheimer’s disease. Front Neurosci. (2019) 13:1443. doi: 10.3389/fnins.2019.01443

PubMed Abstract | Crossref Full Text | Google Scholar

112. Belaidi AA and Bush AI. Iron neurochemistry in alzheimer’s disease and parkinson’s disease: targets for therapeutics. J Neurochem. (2016) 139 Suppl 1:179–97. doi: 10.1111/jnc.13425

PubMed Abstract | Crossref Full Text | Google Scholar

113. Rogers JT, Randall JD, Cahill CM, Eder PS, Huang X, Gunshin H, et al. An iron-responsive element type ii in the 5’-untranslated region of the alzheimer’s amyloid precursor protein transcript. J Biol Chem. (2002) 277:45518–28. doi: 10.1074/jbc.M207435200

PubMed Abstract | Crossref Full Text | Google Scholar

114. Anderson GJ and Frazer DM. Current understanding of iron homeostasis. Am J Clin Nutr. (2017) 106:1559s–66s. doi: 10.3945/ajcn.117.155804

PubMed Abstract | Crossref Full Text | Google Scholar

115. Meyron-Holtz EG, Ghosh MC, Iwai K, LaVaute T, Brazzolotto X, Berger UV, et al. Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J. (2004) 23:386–95. doi: 10.1038/sj.emboj.7600041

PubMed Abstract | Crossref Full Text | Google Scholar

116. Greenough MA. The role of presenilin in protein trafficking and degradation-implications for metal homeostasis. J Mol Neurosci. (2016) 60:289–97. doi: 10.1007/s12031-016-0826-4

PubMed Abstract | Crossref Full Text | Google Scholar

117. Ha C, Ryu J, and Park CB. Metal ions differentially influence the aggregation and deposition of alzheimer’s beta-amyloid on a solid template. Biochemistry. (2007) 46:6118–25. doi: 10.1021/bi7000032

PubMed Abstract | Crossref Full Text | Google Scholar

118. Butterfield DA and Boyd-Kimball D. Oxidative stress, amyloid-B Peptide, and altered key molecular pathways in the pathogenesis and progression of alzheimer’s disease. J Alzheimers Dis. (2018) 62:1345–67. doi: 10.3233/jad-170543

PubMed Abstract | Crossref Full Text | Google Scholar

119. García-Viñuales S, Sciacca MFM, Lanza V, Santoro AM, Grasso G, Tundo GR, et al. The interplay between lipid and Aβ Amyloid homeostasis in alzheimer’s disease: risk factors and therapeutic opportunities. Chem Phys Lipids. (2021) 236:105072. doi: 10.1016/j.chemphyslip.2021.105072

PubMed Abstract | Crossref Full Text | Google Scholar

120. Huang L, McClatchy DB, Maher P, Liang Z, Diedrich JK, Soriano-Castell D, et al. Intracellular amyloid toxicity induces oxytosis/ferroptosis regulated cell death. Cell Death Dis. (2020) 11:828. doi: 10.1038/s41419-020-03020-9

PubMed Abstract | Crossref Full Text | Google Scholar

121. Zhang H, Gao Y, Qiao PF, Zhao FL, and Yan Y. Ppar-A Agonist regulates amyloid-B Generation via inhibiting bace-1 activity in human neuroblastoma sh-sy5y cells transfected with appswe gene. Mol Cell Biochem. (2015) 408:37–46. doi: 10.1007/s11010-015-2480-5

PubMed Abstract | Crossref Full Text | Google Scholar

122. Plascencia-Villa G and Perry G. Preventive and therapeutic strategies in alzheimer’s disease: focus on oxidative stress, redox metals, and ferroptosis. Antioxid Redox Signal. (2021) 34:591–610. doi: 10.1089/ars.2020.8134

PubMed Abstract | Crossref Full Text | Google Scholar

123. Wan W, Cao L, Kalionis B, Murthi P, Xia S, and Guan Y. Iron deposition leads to hyperphosphorylation of tau and disruption of insulin signaling. Front Neurol. (2019) 10:607. doi: 10.3389/fneur.2019.00607

PubMed Abstract | Crossref Full Text | Google Scholar

124. Guo C, Wang P, Zhong ML, Wang T, Huang XS, Li JY, et al. Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the alzheimer transgenic mouse brain. Neurochem Int. (2013) 62:165–72. doi: 10.1016/j.neuint.2012.12.005

PubMed Abstract | Crossref Full Text | Google Scholar

125. Muñoz P, Zavala G, Castillo K, Aguirre P, Hidalgo C, and Núñez MT. Effect of iron on the activation of the mapk/erk pathway in pc12 neuroblastoma cells. Biol Res. (2006) 39:189–90. doi: 10.4067/s0716-97602006000100021

PubMed Abstract | Crossref Full Text | Google Scholar

126. Chan A and Shea TB. Dietary and genetically-induced oxidative stress alter tau phosphorylation: influence of folate and apolipoprotein E deficiency. J Alzheimers Dis. (2006) 9:399–405. doi: 10.3233/jad-2006-9405

PubMed Abstract | Crossref Full Text | Google Scholar

127. Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, et al. Tau deficiency induces parkinsonism with dementia by impairing app-mediated iron export. Nat Med. (2012) 18:291–5. doi: 10.1038/nm.2613

PubMed Abstract | Crossref Full Text | Google Scholar

128. Kawarabayashi T, Shoji M, Younkin LH, Wen-Lang L, Dickson DW, Murakami T, et al. Dimeric amyloid beta protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the tg2576 mouse model of alzheimer’s disease. J Neurosci. (2004) 24:3801–9. doi: 10.1523/jneurosci.5543-03.2004

PubMed Abstract | Crossref Full Text | Google Scholar

129. King ME, Gamblin TC, Kuret J, and Binder LI. Differential assembly of human tau isoforms in the presence of arachidonic acid. J Neurochem. (2000) 74:1749–57. doi: 10.1046/j.1471-4159.2000.0741749.x

PubMed Abstract | Crossref Full Text | Google Scholar

130. Bok E, Leem E, Lee BR, Lee JM, Yoo CJ, Lee EM, et al. Role of the lipid membrane and membrane proteins in tau pathology. Front Cell Dev Biol. (2021) 9:653815. doi: 10.3389/fcell.2021.653815

PubMed Abstract | Crossref Full Text | Google Scholar

131. Louveau A. Cerebral lymphatic drainage: implication in the brain immune privilege. Med Sci (Paris). (2015) 31:953–6. doi: 10.1051/medsci/20153111005

PubMed Abstract | Crossref Full Text | Google Scholar

132. Sevenich L. Brain-resident microglia and blood-borne macrophages orchestrate central nervous system inflammation in neurodegenerative disorders and brain cancer. Front Immunol. (2018) 9:697. doi: 10.3389/fimmu.2018.00697

PubMed Abstract | Crossref Full Text | Google Scholar

133. Singh V, Mitra S, Sharma AK, Gera R, and Ghosh D. Isolation and characterization of microglia from adult mouse brain: selected applications for ex vivo evaluation of immunotoxicological alterations following in vivo xenobiotic exposure. Chem Res Toxicol. (2014) 27:895–903. doi: 10.1021/tx500046k

PubMed Abstract | Crossref Full Text | Google Scholar

134. Amor S, Puentes F, Baker D, and van der Valk P. Inflammation in neurodegenerative diseases. Immunology. (2010) 129:154–69. doi: 10.1111/j.1365-2567.2009.03225.x

PubMed Abstract | Crossref Full Text | Google Scholar

135. Meng FX, Hou JM, and Sun TS. In vivo evaluation of microglia activation by intracranial iron overload in central pain after spinal cord injury. J Orthop Surg Res. (2017) 12:75. doi: 10.1186/s13018-017-0578-z

PubMed Abstract | Crossref Full Text | Google Scholar

136. Holland R, McIntosh AL, Finucane OM, Mela V, Rubio-Araiz A, Timmons G, et al. Inflammatory microglia are glycolytic and iron retentive and typify the microglia in app/ps1 mice. Brain Behav Immun. (2018) 68:183–96. doi: 10.1016/j.bbi.2017.10.017

PubMed Abstract | Crossref Full Text | Google Scholar

137. Kenkhuis B, Somarakis A, de Haan L, Dzyubachyk O, ME IJ, de Miranda N, et al. Iron loading is a prominent feature of activated microglia in alzheimer’s disease patients. Acta Neuropathol Commun. (2021) 9:27. doi: 10.1186/s40478-021-01126-5

PubMed Abstract | Crossref Full Text | Google Scholar

138. Simmons DA, Casale M, Alcon B, Pham N, Narayan N, and Lynch G. Ferritin accumulation in dystrophic microglia is an early event in the development of huntington’s disease. Glia. (2007) 55:1074–84. doi: 10.1002/glia.20526

PubMed Abstract | Crossref Full Text | Google Scholar

139. van Duijn S, Bulk M, van Duinen SG, Nabuurs RJA, van Buchem MA, van der Weerd L, et al. Cortical iron reflects severity of alzheimer’s disease. J Alzheimers Dis. (2017) 60:1533–45. doi: 10.3233/jad-161143

PubMed Abstract | Crossref Full Text | Google Scholar

140. Nnah IC, Lee CH, and Wessling-Resnick M. Iron potentiates microglial interleukin-1β Secretion induced by amyloid-B. J Neurochem. (2020) 154:177–89. doi: 10.1111/jnc.14906

PubMed Abstract | Crossref Full Text | Google Scholar

141. Fernández-Mendívil C, Arreola MA, Hohsfield LA, Green KN, and Lopez MG. Aging and progression of beta-amyloid pathology in alzheimer’s disease correlates with microglial heme-oxygenase-1 overexpression. Antioxidants (Basel). (2020) 9:644. doi: 10.3390/antiox9070644

PubMed Abstract | Crossref Full Text | Google Scholar

142. Long HZ, Zhou ZW, Cheng Y, Luo HY, Li FJ, Xu SG, et al. The role of microglia in alzheimer’s disease from the perspective of immune inflammation and iron metabolism. Front Aging Neurosci. (2022) 14:888989. doi: 10.3389/fnagi.2022.888989

PubMed Abstract | Crossref Full Text | Google Scholar

143. Peters DG, Pollack AN, Cheng KC, Sun D, Saido T, Haaf MP, et al. Dietary lipophilic iron alters amyloidogenesis and microglial morphology in alzheimer’s disease knock-in app mice. Metallomics. (2018) 10:426–43. doi: 10.1039/c8mt00004b

PubMed Abstract | Crossref Full Text | Google Scholar

144. Tsatsanis A, McCorkindale AN, Wong BX, Patrick E, Ryan TM, Evans RW, et al. The acute phase protein lactoferrin is a key feature of alzheimer’s disease and predictor of Aβ Burden through induction of app amyloidogenic processing. Mol Psychiatry. (2021) 26:5516–31. doi: 10.1038/s41380-021-01248-1

PubMed Abstract | Crossref Full Text | Google Scholar

145. Giulian D, Haverkamp LJ, Li J, Karshin WL, Yu J, Tom D, et al. Senile plaques stimulate microglia to release a neurotoxin found in alzheimer brain. Neurochem Int. (1995) 27:119–37. doi: 10.1016/0197-0186(95)00067-i

PubMed Abstract | Crossref Full Text | Google Scholar

146. Giulian D, Haverkamp LJ, Yu JH, Karshin W, Tom D, Li J, et al. Specific domains of beta-amyloid from alzheimer plaque elicit neuron killing in human microglia. J Neurosci. (1996) 16:6021–37. doi: 10.1523/jneurosci.16-19-06021.1996

PubMed Abstract | Crossref Full Text | Google Scholar

147. Smith MA, Zhu X, Tabaton M, Liu G, McKeel DW Jr., Cohen ML, et al. Increased iron and free radical generation in preclinical alzheimer disease and mild cognitive impairment. J Alzheimers Dis. (2010) 19:363–72. doi: 10.3233/jad-2010-1239

PubMed Abstract | Crossref Full Text | Google Scholar

148. Neumann P, Lenz DE, Streit WJ, and Bechmann I. Is microglial dystrophy a form of cellular senescence? An analysis of senescence markers in the aged human brain. Glia. (2023) 71:377–90. doi: 10.1002/glia.24282

PubMed Abstract | Crossref Full Text | Google Scholar

149. Connor JR, Menzies SL, St Martin SM, and Mufson EJ. A histochemical study of iron, transferrin, and ferritin in alzheimer’s diseased brains. J Neurosci Res. (1992) 31:75–83. doi: 10.1002/jnr.490310111

PubMed Abstract | Crossref Full Text | Google Scholar

150. Streit WJ, Braak H, Del Tredici K, Leyh J, Lier J, Khoshbouei H, et al. Microglial activation occurs late during preclinical alzheimer’s disease. Glia. (2018) 66:2550–62. doi: 10.1002/glia.23510

PubMed Abstract | Crossref Full Text | Google Scholar

151. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and alzheimer’s disease. Neurobiol Aging. (2000) 21:383–421. doi: 10.1016/s0197-4580(00)00124-x

PubMed Abstract | Crossref Full Text | Google Scholar

152. Streit WJ. Microglia and alzheimer’s disease pathogenesis. J Neurosci Res. (2004) 77:1–8. doi: 10.1002/jnr.20093

PubMed Abstract | Crossref Full Text | Google Scholar

153. Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, et al. Ineffective phagocytosis of amyloid-beta by macrophages of alzheimer’s disease patients. J Alzheimers Dis. (2005) 7:221–32. doi: 10.3233/jad-2005-7304

PubMed Abstract | Crossref Full Text | Google Scholar

154. Njie EG, Boelen E, Stassen FR, Steinbusch HW, Borchelt DR, and Streit WJ. Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging. (2012) 33:195. doi: 10.1016/j.neurobiolaging.2010.05.008

PubMed Abstract | Crossref Full Text | Google Scholar

155. Kam TI, Gwon Y, and Jung YK. Amyloid beta receptors responsible for neurotoxicity and cellular defects in alzheimer’s disease. Cell Mol Life Sci. (2014) 71:4803–13. doi: 10.1007/s00018-014-1706-0

PubMed Abstract | Crossref Full Text | Google Scholar

156. Flanary BE, Sammons NW, Nguyen C, Walker D, and Streit WJ. Evidence that aging and amyloid promote microglial cell senescence. Rejuvenation Res. (2007) 10:61–74. doi: 10.1089/rej.2006.9096

PubMed Abstract | Crossref Full Text | Google Scholar

157. Dringen R. Oxidative and antioxidative potential of brain microglial cells. Antioxid Redox Signal. (2005) 7:1223–33. doi: 10.1089/ars.2005.7.1223

PubMed Abstract | Crossref Full Text | Google Scholar

158. Chatterjee S, Noack H, Possel H, Keilhoff G, and Wolf G. Glutathione levels in primary glial cultures: monochlorobimane provides evidence of cell type-specific distribution. Glia. (1999) 27:152–61. doi: 10.1002/(SICI)1098-1136(199908)27:2<152::AID-GLIA5>3.0.CO;2-Q

PubMed Abstract | Crossref Full Text | Google Scholar

159. Hirrlinger J, Gutterer JM, Kussmaul L, Hamprecht B, and Dringen R. Microglial cells in culture express a prominent glutathione system for the defense against reactive oxygen species. Dev Neurosci. (2000) 22:384–92. doi: 10.1159/000017464

PubMed Abstract | Crossref Full Text | Google Scholar

160. Chatterjee S, Noack H, Possel H, and Wolf G. Induction of nitric oxide synthesis lowers intracellular glutathione in microglia of primary glial cultures. Glia. (2000) 29:98–101. doi: 10.1002/(SICI)1098-1136(20000101)29:1<98::AID-GLIA10>3.0.CO;2-B

PubMed Abstract | Crossref Full Text | Google Scholar

161. Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the national alzheimer’s coordinating centre. Brain. (2013) 136:2697–706. doi: 10.1093/brain/awt188

PubMed Abstract | Crossref Full Text | Google Scholar

162. Newcombe EA, Camats-Perna J, Silva ML, Valmas N, Huat TJ, and Medeiros R. Inflammation: the link between comorbidities, genetics, and alzheimer’s disease. J Neuroinflamm. (2018) 15:276. doi: 10.1186/s12974-018-1313-3

PubMed Abstract | Crossref Full Text | Google Scholar

163. Leng F and Edison P. Neuroinflammation and microglial activation in alzheimer disease: where do we go from here? Nat Rev Neurol. (2021) 17:157–72. doi: 10.1038/s41582-020-00435-y

PubMed Abstract | Crossref Full Text | Google Scholar

164. Dusek P, Hofer T, Alexander J, Roos PM, and Aaseth JO. Cerebral iron deposition in neurodegeneration. Biomolecules. (2022) 12:714. doi: 10.3390/biom12050714

PubMed Abstract | Crossref Full Text | Google Scholar

165. Hohnholt MC and Dringen R. Uptake and metabolism of iron and iron oxide nanoparticles in brain astrocytes. Biochem Soc Trans. (2013) 41:1588–92. doi: 10.1042/bst20130114

PubMed Abstract | Crossref Full Text | Google Scholar

166. Burkhart A, Skjørringe T, Johnsen KB, Siupka P, Thomsen LB, Nielsen MS, et al. Expression of Iron-Related Proteins at the Neurovascular Unit Supports Reduction and Reoxidation of Iron for Transport through the Blood-Brain Barrier. Mol Neurobiol. (2016) 53:7237–53. doi: 10.1007/s12035-015-9582-7

PubMed Abstract | Crossref Full Text | Google Scholar

167. Huang E, Ong WY, Go ML, and Connor JR. Upregulation of iron regulatory proteins and divalent metal transporter-1 isoforms in the rat hippocampus after kainate induced neuronal injury. Exp Brain Res. (2006) 170:376–86. doi: 10.1007/s00221-005-0220-x

PubMed Abstract | Crossref Full Text | Google Scholar

168. Pelizzoni I, Zacchetti D, Campanella A, Grohovaz F, and Codazzi F. Iron uptake in quiescent and inflammation-activated astrocytes: A potentially neuroprotective control of iron burden. Biochim Biophys Acta. (2013) 1832:1326–33. doi: 10.1016/j.bbadis.2013.04.007

PubMed Abstract | Crossref Full Text | Google Scholar

169. Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, et al. Coordinate regulation of glutathione biosynthesis and release by nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci. (2003) 23:3394–406. doi: 10.1523/jneurosci.23-08-03394.2003

PubMed Abstract | Crossref Full Text | Google Scholar

170. Iwata-Ichikawa E, Kondo Y, Miyazaki I, Asanuma M, and Ogawa N. Glial Cells Protect Neurons against Oxidative Stress Via Transcriptional up-Regulation of the Glutathione Synthesis. J Neurochem. (1999) 72:2334–44. doi: 10.1046/j.1471-4159.1999.0722334.x

PubMed Abstract | Crossref Full Text | Google Scholar

171. Cai Z, Wan CQ, and Liu Z. Astrocyte and alzheimer’s disease. J Neurol. (2017) 264:2068–74. doi: 10.1007/s00415-017-8593-x

PubMed Abstract | Crossref Full Text | Google Scholar

172. De Domenico I, McVey Ward D, and Kaplan J. Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nat Rev Mol Cell Biol. (2008) 9:72–81. doi: 10.1038/nrm2295

PubMed Abstract | Crossref Full Text | Google Scholar

173. McCarthy RC and Kosman DJ. Ferroportin and exocytoplasmic ferroxidase activity are required for brain microvascular endothelial cell iron efflux. J Biol Chem. (2013) 288:17932–40. doi: 10.1074/jbc.M113.455428

PubMed Abstract | Crossref Full Text | Google Scholar

174. Moos T, Skjoerringe T, Gosk S, and Morgan EH. Brain Capillary Endothelial Cells Mediate Iron Transport into the Brain by Segregating Iron from Transferrin without the Involvement of Divalent Metal Transporter 1. J Neurochem. (2006) 98:1946–58. doi: 10.1111/j.1471-4159.2006.04023.x

PubMed Abstract | Crossref Full Text | Google Scholar

175. Raub TJ and Newton CR. Recycling kinetics and transcytosis of transferrin in primary cultures of bovine brain microvessel endothelial cells. J Cell Physiol. (1991) 149:141–51. doi: 10.1002/jcp.1041490118

PubMed Abstract | Crossref Full Text | Google Scholar

176. Descamps L, Dehouck MP, Torpier G, and Cecchelli R. Receptor-mediated transcytosis of transferrin through blood-brain barrier endothelial cells. Am J Physiol. (1996) 270:H1149–58. doi: 10.1152/ajpheart.1996.270.4.H1149

PubMed Abstract | Crossref Full Text | Google Scholar

177. Bateman RJ, Barthélemy NR, and Horie K. Another step forward in blood-based diagnostics for alzheimer’s disease. Nat Med. (2020) 26:314–6. doi: 10.1038/s41591-020-0797-4

PubMed Abstract | Crossref Full Text | Google Scholar

178. Frisoni GB, Fox NC, Jack CR Jr., Scheltens P, and Thompson PM. The clinical use of structural mri in alzheimer disease. Nat Rev Neurol. (2010) 6:67–77. doi: 10.1038/nrneurol.2009.215

PubMed Abstract | Crossref Full Text | Google Scholar

179. Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, et al. Accelerated alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med. (1998) 4:97–100. doi: 10.1038/nm0198-097

PubMed Abstract | Crossref Full Text | Google Scholar

180. Johnson KA, Fox NC, Sperling RA, and Klunk WE. Brain imaging in alzheimer disease. Cold Spring Harb Perspect Med. (2012) 2:a006213. doi: 10.1101/cshperspect.a006213

PubMed Abstract | Crossref Full Text | Google Scholar

181. Frisoni GB, Jack CR Jr., Bocchetta M, Bauer C, Frederiksen KS, Liu Y, et al. The eadc-adni harmonized protocol for manual hippocampal segmentation on magnetic resonance: evidence of validity. Alzheimers Dement. (2015) 11:111–25. doi: 10.1016/j.jalz.2014.05.1756

PubMed Abstract | Crossref Full Text | Google Scholar

182. Boccardi M, Bocchetta M, Apostolova LG, Barnes J, Bartzokis G, Corbetta G, et al. Delphi definition of the eadc-adni harmonized protocol for hippocampal segmentation on magnetic resonance. Alzheimers Dement. (2015) 11:126–38. doi: 10.1016/j.jalz.2014.02.009

PubMed Abstract | Crossref Full Text | Google Scholar

183. Tran D, DiGiacomo P, Born DE, Georgiadis M, and Zeineh M. Iron and alzheimer’s disease: from pathology to imaging. Front Hum Neurosci. (2022) 16:838692. doi: 10.3389/fnhum.2022.838692

PubMed Abstract | Crossref Full Text | Google Scholar

184. Cilliers K. Trace element alterations in alzheimer’s disease: A review. Clin Anat. (2021) 34:766–73. doi: 10.1002/ca.23727

PubMed Abstract | Crossref Full Text | Google Scholar

185. Bai R, Guo J, Ye XY, Xie Y, and Xie T. Oxidative stress: the core pathogenesis and mechanism of alzheimer’s disease. Ageing Res Rev. (2022) 77:101619. doi: 10.1016/j.arr.2022.101619

PubMed Abstract | Crossref Full Text | Google Scholar

186. Peña-Bautista C, Vigor C, Galano JM, Oger C, Durand T, Ferrer I, et al. Plasma lipid peroxidation biomarkers for early and non-invasive alzheimer disease detection. Free Radic Biol Med. (2018) 124:388–94. doi: 10.1016/j.freeradbiomed.2018.06.038

PubMed Abstract | Crossref Full Text | Google Scholar

187. Terluk MR, Ebeling MC, Fisher CR, Kapphahn RJ, Yuan C, Kartha RV, et al. N-acetyl-L-cysteine protects human retinal pigment epithelial cells from oxidative damage: implications for age-related macular degeneration. Oxid Med Cell Longev. (2019) 2019:5174957. doi: 10.1155/2019/5174957

PubMed Abstract | Crossref Full Text | Google Scholar

188. Tardiolo G, Bramanti P, and Mazzon E. Overview on the effects of N-acetylcysteine in neurodegenerative diseases. Molecules. (2018) 23:3305. doi: 10.3390/molecules23123305

PubMed Abstract | Crossref Full Text | Google Scholar

189. Chen L, Dar NJ, Na R, McLane KD, Yoo K, Han X, et al. Enhanced defense against ferroptosis ameliorates cognitive impairment and reduces neurodegeneration in 5xfad mice. Free Radic Biol Med. (2022) 180:1–12. doi: 10.1016/j.freeradbiomed.2022.01.002

PubMed Abstract | Crossref Full Text | Google Scholar

190. Zhang YH, Wang DW, Xu SF, Zhang S, Fan YG, Yang YY, et al. A-lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301s tau transgenic mice. Redox Biol. (2018) 14:535–48. doi: 10.1016/j.redox.2017.11.001

PubMed Abstract | Crossref Full Text | Google Scholar

191. Sui X, Zhang R, Liu S, Duan T, Zhai L, Zhang M, et al. Rsl3 drives ferroptosis through gpx4 inactivation and ros production in colorectal cancer. Front Pharmacol. (2018) 9:1371. doi: 10.3389/fphar.2018.01371

PubMed Abstract | Crossref Full Text | Google Scholar

192. Qu XX, He JH, Cui ZQ, Yang T, and Sun XH. Ppar-A Agonist gw7647 protects against oxidative stress and iron deposit via gpx4 in a transgenic mouse model of alzheimer’s diseases. ACS Chem Neurosci. (2022) 13:207–16. doi: 10.1021/acschemneuro.1c00516

PubMed Abstract | Crossref Full Text | Google Scholar

193. Yoo MH, Gu X, Xu XM, Kim JY, Carlson BA, Patterson AD, et al. Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in alzheimer’s disease. Antioxid Redox Signal. (2010) 12:819–27. doi: 10.1089/ars.2009.2891

PubMed Abstract | Crossref Full Text | Google Scholar

194. Hill RL, Singh IN, Wang JA, Kulbe JR, and Hall ED. Protective effects of phenelzine administration on synaptic and non-synaptic cortical mitochondrial function and lipid peroxidation-mediated oxidative damage following tbi in young adult male rats. Exp Neurol. (2020) 330:113322. doi: 10.1016/j.expneurol.2020.113322

PubMed Abstract | Crossref Full Text | Google Scholar

195. Zheng J and Conrad M. The metabolic underpinnings of ferroptosis. Cell Metab. (2020) 32:920–37. doi: 10.1016/j.cmet.2020.10.011

PubMed Abstract | Crossref Full Text | Google Scholar

196. Ates G, Goldberg J, Currais A, and Maher P. Cms121, a fatty acid synthase inhibitor, protects against excess lipid peroxidation and inflammation and alleviates cognitive loss in a transgenic mouse model of alzheimer’s disease. Redox Biol. (2020) 36:101648. doi: 10.1016/j.redox.2020.101648

PubMed Abstract | Crossref Full Text | Google Scholar

197. Zhu ZY, Liu YD, Gong Y, Jin W, Topchiy E, Turdi S, et al. Mitochondrial aldehyde dehydrogenase (Aldh2) rescues cardiac contractile dysfunction in an app/ps1 murine model of alzheimer’s disease via inhibition of acsl4-dependent ferroptosis. Acta Pharmacol Sin. (2022) 43:39–49. doi: 10.1038/s41401-021-00635-2

PubMed Abstract | Crossref Full Text | Google Scholar

198. Wang L, Li N, Shi FX, Xu WQ, Cao Y, Lei Y, et al. Upregulation of ampk ameliorates alzheimer’s disease-like tau pathology and memory impairment. Mol Neurobiol. (2020) 57:3349–61. doi: 10.1007/s12035-020-01955-w

PubMed Abstract | Crossref Full Text | Google Scholar

199. Belaidi AA, Bush AI, and Ayton S. Apolipoprotein E in alzheimer’s disease: molecular insights and therapeutic opportunities. Mol Neurodegener. (2025) 20:47. doi: 10.1186/s13024-025-00843-y

PubMed Abstract | Crossref Full Text | Google Scholar

200. Kanatsu K and Tomita T. Molecular mechanisms of the genetic risk factors in pathogenesis of alzheimer disease. Front Biosci (Landmark Ed). (2017) 22:180–92. doi: 10.2741/4480

PubMed Abstract | Crossref Full Text | Google Scholar

201. Belaidi AA, Masaldan S, Southon A, Kalinowski P, Acevedo K, Appukuttan AT, et al. Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy. Mol Psychiatry. (2024) 29:211–20. doi: 10.1038/s41380-022-01568-w

PubMed Abstract | Crossref Full Text | Google Scholar

202. Mishima E. The E2f1-ireb2 axis regulates neuronal ferroptosis in cerebral ischemia. Hypertens Res. (2022) 45:1085–6. doi: 10.1038/s41440-021-00837-5

PubMed Abstract | Crossref Full Text | Google Scholar

203. Coon KD, Siegel AM, Yee SJ, Dunckley TL, Mueller C, Nagra RM, et al. Preliminary demonstration of an allelic association of the ireb2 gene with alzheimer’s disease. J Alzheimers Dis. (2006) 9:225–33. doi: 10.3233/jad-2006-9301

PubMed Abstract | Crossref Full Text | Google Scholar

204. Greenough MA, Lane DJR, Balez R, Anastacio HTD, Zeng Z, Ganio K, et al. Selective ferroptosis vulnerability due to familial alzheimer’s disease presenilin mutations. Cell Death Differ. (2022) 29:2123–36. doi: 10.1038/s41418-022-01003-1

PubMed Abstract | Crossref Full Text | Google Scholar

205. Zoghbi HY, Beaud, et al. Epigenetics and human disease. Cold Spring Harb Perspect Biol. (2016) 8:a019497. doi: 10.1101/cshperspect.a019497

PubMed Abstract | Crossref Full Text | Google Scholar

206. Lu X, Deng Y, Yu D, Cao H, Wang L, Liu L, et al. Histone acetyltransferase P300 mediates histone acetylation of ps1 and bace1 in a cellular model of alzheimer’s disease. PloS One. (2014) 9:e103067. doi: 10.1371/journal.pone.0103067

PubMed Abstract | Crossref Full Text | Google Scholar

207. Marques SC, Lemos R, Ferreiro E, Martins M, de Mendonça A, Santana I, et al. Epigenetic regulation of bace1 in alzheimer’s disease patients and in transgenic mice. Neuroscience. (2012) 220:256–66. doi: 10.1016/j.neuroscience.2012.06.029

PubMed Abstract | Crossref Full Text | Google Scholar

208. Mastroeni D, Delvaux E, Nolz J, Tan Y, Grover A, Oddo S, et al. Aberrant intracellular localization of H3k4me3 demonstrates an early epigenetic phenomenon in alzheimer’s disease. Neurobiol Aging. (2015) 36:3121–9. doi: 10.1016/j.neurobiolaging.2015.08.017

PubMed Abstract | Crossref Full Text | Google Scholar

209. Sui S, Zhang J, Xu S, Wang Q, Wang P, and Pang D. Ferritinophagy is required for the induction of ferroptosis by the bromodomain protein brd4 inhibitor (+)-jq1 in cancer cells. Cell Death Dis. (2019) 10:331. doi: 10.1038/s41419-019-1564-7

PubMed Abstract | Crossref Full Text | Google Scholar

210. Zhang X, Sui S, Wang L, Li H, Zhang L, Xu S, et al. Inhibition of tumor propellant glutathione peroxidase 4 induces ferroptosis in cancer cells and enhances anticancer effect of cisplatin. J Cell Physiol. (2020) 235:3425–37. doi: 10.1002/jcp.29232

PubMed Abstract | Crossref Full Text | Google Scholar

211. Zhang Y, Shi J, Liu X, Feng L, Gong Z, Koppula P, et al. Bap1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol. (2018) 20:1181–92. doi: 10.1038/s41556-018-0178-0

PubMed Abstract | Crossref Full Text | Google Scholar

212. Khan S, Shukla S, Sinha S, and Meeran SM. Epigenetic targets in cancer and aging: dietary and therapeutic interventions. Expert Opin Ther Targets. (2016) 20:689–703. doi: 10.1517/14728222.2016.1132702

PubMed Abstract | Crossref Full Text | Google Scholar

213. Oliveira AM, Hemstedt TJ, and Bading H. Rescue of aging-associated decline in dnmt3a2 expression restores cognitive abilities. Nat Neurosci. (2012) 15:1111–3. doi: 10.1038/nn.3151

PubMed Abstract | Crossref Full Text | Google Scholar

214. Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P, et al. Evidence that DNA (Cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem. (2006) 281:15763–73. doi: 10.1074/jbc.M511767200

PubMed Abstract | Crossref Full Text | Google Scholar

215. Chouliaras L, Kenis G, Visser PJ, Scheltens P, Tsolaki M, Jones RW, et al. Dnmt3a moderates cognitive decline in subjects with mild cognitive impairment: replicated evidence from two mild cognitive impairment cohorts. Epigenomics. (2015) 7:533–7. doi: 10.2217/epi.15.22

PubMed Abstract | Crossref Full Text | Google Scholar

216. Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, and Rogers J. Epigenetic changes in alzheimer’s disease: decrements in DNA methylation. Neurobiol Aging. (2010) 31:2025–37. doi: 10.1016/j.neurobiolaging.2008.12.005

PubMed Abstract | Crossref Full Text | Google Scholar

217. Chen KL, Wang SS, Yang YY, Yuan RY, Chen RM, and Hu CJ. The epigenetic effects of amyloid-beta(1-40) on global DNA and neprilysin genes in murine cerebral endothelial cells. Biochem Biophys Res Commun. (2009) 378:57–61. doi: 10.1016/j.bbrc.2008.10.173

PubMed Abstract | Crossref Full Text | Google Scholar

218. Gomaa A, Peng D, Chen Z, Soutto M, Abouelezz K, Corvalan A, et al. Epigenetic regulation of aurka by mir-4715-3p in upper gastrointestinal cancers. Sci Rep. (2019) 9:16970. doi: 10.1038/s41598-019-53174-6

PubMed Abstract | Crossref Full Text | Google Scholar

219. Lukiw WJ, Surjyadipta B, Dua P, and Alexandrov PN. Common micro rnas (Mirnas) target complement factor H (Cfh) regulation in alzheimer’s disease (Ad) and in age-related macular degeneration (Amd). Int J Biochem Mol Biol. (2012) 3:105–16.

PubMed Abstract | Google Scholar

220. Lardenoije R, Iatrou A, Kenis G, Kompotis K, Steinbusch HW, Mastroeni D, et al. The epigenetics of aging and neurodegeneration. Prog Neurobiol. (2015) 131:21–64. doi: 10.1016/j.pneurobio.2015.05.002

PubMed Abstract | Crossref Full Text | Google Scholar

221. Luo M, Wu L, Zhang K, Wang H, Zhang T, Gutierrez L, et al. Mir-137 regulates ferroptosis by targeting glutamine transporter slc1a5 in melanoma. Cell Death Differ. (2018) 25:1457–72. doi: 10.1038/s41418-017-0053-8

PubMed Abstract | Crossref Full Text | Google Scholar

222. Zhang H, Deng T, Liu R, Ning T, Yang H, Liu D, et al. Caf secreted mir-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer. (2020) 19:43. doi: 10.1186/s12943-020-01168-8

PubMed Abstract | Crossref Full Text | Google Scholar

223. Chen D, Hu J, Yang S, Xie P, Ji M, Zhang Z, et al. Mechanistic studies of the beneficial effects of anshen dingzhi prescription for ptsd treatment: roles of the fkbp5-ikkα-nf-Kb-nlrp3 signaling pathway. Acupunct Herb Med. (2025) 5:316–27. doi: 10.1097/hm9.0000000000000164

Crossref Full Text | Google Scholar

224. Gleason A and Bush AI. Iron and ferroptosis as therapeutic targets in alzheimer’s disease. Neurotherapeutics. (2021) 18:252–64. doi: 10.1007/s13311-020-00954-y

PubMed Abstract | Crossref Full Text | Google Scholar

225. Reddy PH, Manczak M, Yin X, Grady MC, Mitchell A, Tonk S, et al. Protective effects of Indian spice curcumin against amyloid-B in alzheimer’s disease. J Alzheimers Dis. (2018) 61:843–66. doi: 10.3233/jad-170512

PubMed Abstract | Crossref Full Text | Google Scholar

226. Ege D. Action mechanisms of curcumin in alzheimer’s disease and its brain targeted delivery. Materials (Basel). (2021) 14:3332. doi: 10.3390/ma14123332

PubMed Abstract | Crossref Full Text | Google Scholar

227. Tang M and Taghibiglou C. The mechanisms of action of curcumin in alzheimer’s disease. J Alzheimers Dis. (2017) 58:1003–16. doi: 10.3233/jad-170188

PubMed Abstract | Crossref Full Text | Google Scholar

228. Feng H, Schorpp K, Jin J, Yozwiak CE, Hoffstrom BG, Decker AM, et al. Transferrin receptor is a specific ferroptosis marker. Cell Rep. (2020) 30:3411–23.e7. doi: 10.1016/j.celrep.2020.02.049

PubMed Abstract | Crossref Full Text | Google Scholar

229. Hider RC and Hoffbrand AV. The role of deferiprone in iron chelation. N Engl J Med. (2018) 379:2140–50. doi: 10.1056/NEJMra1800219

PubMed Abstract | Crossref Full Text | Google Scholar

230. Meloni A, Pistoia L, Ricchi P, Allò M, Rosso R, Cuccia L, et al. Prospective changes of pancreatic iron in patients with thalassemia major and association with chelation therapy. Blood Adv. (2023) 7:2237–40. doi: 10.1182/bloodadvances.2022008805

PubMed Abstract | Crossref Full Text | Google Scholar

231. Yang HX, Liu QP, Zhou YX, Chen YY, An P, Xing YZ, et al. Forsythiasides: A review of the pharmacological effects. Front Cardiovasc Med. (2022) 9:971491. doi: 10.3389/fcvm.2022.971491

PubMed Abstract | Crossref Full Text | Google Scholar

232. Zhou M, Zhao X, Liao L, Deng Y, Liu M, Wang J, et al. Forsythiaside a regulates activation of hepatic stellate cells by inhibiting nox4-dependent ros. Oxid Med Cell Longev. (2022) 2022:9938392. doi: 10.1155/2022/9938392

PubMed Abstract | Crossref Full Text | Google Scholar

233. Chen L, Yan Y, Chen T, Zhang L, Gao X, Du C, et al. Forsythiaside prevents B-amyloid-induced hippocampal slice injury by upregulating 2-arachidonoylglycerol via cannabinoid receptor 1-dependent nf-Kb pathway. Neurochem Int. (2019) 125:57–66. doi: 10.1016/j.neuint.2019.02.008

PubMed Abstract | Crossref Full Text | Google Scholar

234. Wang HM, Wang LW, Liu XM, Li CL, Xu SP, and Farooq AD. Neuroprotective effects of forsythiaside on learning and memory deficits in senescence-accelerated mouse prone (Samp8) mice. Pharmacol Biochem Behav. (2013) 105:134–41. doi: 10.1016/j.pbb.2012.12.016

PubMed Abstract | Crossref Full Text | Google Scholar

235. Terlizzi M, Colarusso C, Di Maio U, Pinto A, and Sorrentino R. The combination of N-acetyl-L-cysteine, pelargonium sidoides and justicia adhatoda (Naxx) exerts bacteriostatic activity against S. Aureus and E. Coli. Nat Prod Res. (2021) 35:5360–3. doi: 10.1080/14786419.2020.1761359

PubMed Abstract | Crossref Full Text | Google Scholar

236. Wang ZH, Xiang J, Liu X, Yu SP, Manfredsson FP, Sandoval IM, et al. Deficiency in bdnf/trkb neurotrophic activity stimulates Δ-secretase by upregulating C/ebpβ in alzheimer’s disease. Cell Rep. (2019) 28:655–69.e5. doi: 10.1016/j.celrep.2019.06.054

PubMed Abstract | Crossref Full Text | Google Scholar

237. Miotto G, Rossetto M, Di Paolo ML, Orian L, Venerando R, Roveri A, et al. Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol. (2020) 28:101328. doi: 10.1016/j.redox.2019.101328

PubMed Abstract | Crossref Full Text | Google Scholar

238. Nagu P, Sharma V, Behl T, Pathan AKA, and Mehta V. Molecular insights to the wnt signaling during alzheimer’s disorder: A potential target for therapeutic interventions. J Mol Neurosci. (2022) 72:679–90. doi: 10.1007/s12031-021-01940-5

PubMed Abstract | Crossref Full Text | Google Scholar

239. Ahlemeyer B and Krieglstein J. Pharmacological studies supporting the therapeutic use of ginkgo biloba extract for alzheimer’s disease. Pharmacopsychiatry. (2003) 36 Suppl 1:S8–14. doi: 10.1055/s-2003-40454

PubMed Abstract | Crossref Full Text | Google Scholar

240. Yang Y, Chen J, Gao Q, Shan X, Wang J, and Lv Z. Study on the attenuated effect of ginkgolide B on ferroptosis in high fat diet induced nonalcoholic fatty liver disease. Toxicology. (2020) 445:152599. doi: 10.1016/j.tox.2020.152599

PubMed Abstract | Crossref Full Text | Google Scholar

241. Liao ZL, Su H, Tan YF, Qiu YJ, Zhu JP, Chen Y, et al. Salidroside Protects Pc-12 Cells against Amyloid B-Induced Apoptosis by Activation of The erk1/2 and Akt Signaling Pathways. Int J Mol Med. (2019) 43:1769–77. doi: 10.3892/ijmm.2019.4088

PubMed Abstract | Crossref Full Text | Google Scholar

242. Shao L, Dong C, Geng D, He Q, and Shi Y. Ginkgolide B protects against cognitive impairment in senescence-accelerated P8 mice by mitigating oxidative stress, inflammation and ferroptosis. Biochem Biophys Res Commun. (2021) 572:7–14. doi: 10.1016/j.bbrc.2021.07.081

PubMed Abstract | Crossref Full Text | Google Scholar

243. Wang HM, Zhang T, Huang JK, Xiang JY, Chen JJ, Fu JL, et al. Edaravone attenuates the proinflammatory response in amyloid-B-treated microglia by inhibiting nlrp3 inflammasome-mediated il-1β Secretion. Cell Physiol Biochem. (2017) 43:1113–25. doi: 10.1159/000481753

PubMed Abstract | Crossref Full Text | Google Scholar

244. Zhang GL, Zhang L, Guo YY, Ma ZL, Wang HY, Li T, et al. Protective effect of edaravone against Aβ25-35-induced mitochondrial oxidative damage in sh-sy5y cells. Cell Mol Biol (Noisy-le-grand). (2017) 63:36–42. doi: 10.14715/cmb/2017.63.5.8

PubMed Abstract | Crossref Full Text | Google Scholar

245. Guo S, Lei Q, Guo H, Yang Q, Xue Y, and Chen R. Edaravone attenuates Aβ 1-42-induced inflammatory damage and ferroptosis in ht22 cells. Neurochem Res. (2023) 48:570–8. doi: 10.1007/s11064-022-03782-y

PubMed Abstract | Crossref Full Text | Google Scholar

246. Joffre C, Rey C, and Layé S. N-3 polyunsaturated fatty acids and the resolution of neuroinflammation. Front Pharmacol. (2019) 10:1022. doi: 10.3389/fphar.2019.01022

PubMed Abstract | Crossref Full Text | Google Scholar

247. Yassine HN, Braskie MN, Mack WJ, Castor KJ, Fonteh AN, Schneider LS, et al. Association of docosahexaenoic acid supplementation with alzheimer disease stage in apolipoprotein E E4 carriers: A review. JAMA Neurol. (2017) 74:339–47. doi: 10.1001/jamaneurol.2016.4899

PubMed Abstract | Crossref Full Text | Google Scholar

248. Bahn G, Park JS, Yun UJ, Lee YJ, Choi Y, Park JS, et al. Nrf2/are pathway negatively regulates bace1 expression and ameliorates cognitive deficits in mouse alzheimer’s models. Proc Natl Acad Sci U.S.A. (2019) 116:12516–23. doi: 10.1073/pnas.1819541116

PubMed Abstract | Crossref Full Text | Google Scholar

249. Kobayashi M and Yamamoto M. Nrf2-keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul. (2006) 46:113–40. doi: 10.1016/j.advenzreg.2006.01.007

PubMed Abstract | Crossref Full Text | Google Scholar

250. Ma S, Zhou X, Wang Y, Li Z, Wang Y, Shi J, et al. Mg53 protein rejuvenates huc-mscs and facilitates their therapeutic effects in ad mice by activating nrf2 signaling pathway. Redox Biol. (2022) 53:102325. doi: 10.1016/j.redox.2022.102325

PubMed Abstract | Crossref Full Text | Google Scholar

251. Gunesch S, Hoffmann M, Kiermeier C, Fischer W, Pinto AFM, Maurice T, et al. 7-O-esters of taxifolin with pronounced and overadditive effects in neuroprotection, anti-neuroinflammation, and amelioration of short-term memory impairment in vivo. Redox Biol. (2020) 29:101378. doi: 10.1016/j.redox.2019.101378

PubMed Abstract | Crossref Full Text | Google Scholar

252. Selkoe DJ. Alzheimer’s disease. Cold Spring Harb Perspect Biol. (2011) 3:a004457. doi: 10.1101/cshperspect.a004457

PubMed Abstract | Crossref Full Text | Google Scholar