Ferroptosis in diabetic retinopathy: from pathogenic mechanisms to translational prospects

Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Despite ongoing revisions in the prevention and treatment of DR, optimal treatment strategies have yet to be established. Revealing the pathological changes and molecular mechanisms of DR is the cornerstone for exploring new therapeutic strategies. Ferroptosis, a new type of programmed cell death proposed in recent years, is characterized mainly by reactive oxygen species and iron-mediated lipid peroxidation. As studies progress, growing evidence has highlighted the involvement of ferroptosis, a newly identified programmed cell death pathway, in the development and pathological mechanisms of DR. The purpose of this review is to discuss the known underlying mechanisms of ferroptosis and elucidate its role in the pathogenesis of DR. Additionally, it explores the abnormal manifestations of iron metabolism and related signaling pathways in DR. Finally, we also summarize the potential compounds that may act as ferroptosis inhibitors in DR in the future. By synthesizing these aspects, this review aims to provide insights for a deeper understanding of the relationship between ferroptosis and DR, as well as potential prevention and treatment strategies.

1 Introduction

Diabetic retinopathy (DR), the most prevalent microvascular complication of diabetes in the ocular fundus, severely compromises patients’ visual function and quality of life. It ranks among the leading causes of irreversible vision impairment and blindness worldwide. The pathogenesis and pathological progression of DR remain incompletely elucidated but are believed to involve multifactorial mechanisms such as inflammatory damage, ischemia, hypoxia, and oxidative stress (1). The blood-retinal barrier (BRB) plays an essential role in maintaining retinal homeostasis. Breakdown of the BRB represents a fundamental pathological event in DR, which is preceded by early core pathological changes including pericyte loss, endothelial cell dysfunction, and basement membrane thickening. These alterations disrupt retinal microcirculation, leading to increased capillary endothelial permeability, extravasation of plasma proteins, and accumulation of advanced glycation end products (AGEs) in the retinal tissue. As the disease advances, retinal hypoxia-ischemia exacerbates, triggering a cascade of pathological alterations including capillary occlusion, aberrant intraretinal and subretinal neovascularization, and neuroretinal degeneration (2).

Ferroptosis is a distinct form of regulated cell death that is mechanistically and morphologically distinguishable from apoptosis, necrosis, and autophagy (3). This iron-dependent programmed cell death process is characterized by the accumulation of lethal lipid peroxides. Cells undergoing ferroptosis display unique ultrastructural features, such as shrinkage or disappearance of mitochondrial cristae, increased mitochondrial membrane density, and rupture of the plasma membrane. Key biochemical hallmarks include dysregulated iron homeostasis, massive reactive oxygen species (ROS) generation, and suppression of the cystine/glutamate antiporter system (System Xc^-). The core regulatory axes of ferroptosis primarily involve redox balance, lipid metabolism, iron regulation, and mitochondrial function (4–6).

Accumulating evidence indicates that ferroptosis critically contributes to the progression of diabetes and its complications via mechanisms involving lipid peroxidation and inflammation-activated neovascularization (7, 8). Substantial studies have documented the occurrence of ferroptosis in clinical DR specimens, as well as in experimental DR animal and cellular models (9–12). Targeting ferroptosis may thus represent a novel therapeutic avenue for DR. In this review, we systematically examine the molecular mechanisms of ferroptosis, discuss its pathophysiological implications and associated signaling networks in DR, and evaluate the potential of ferroptosis inhibition as a treatment strategy for DR.

2 Molecular mechanisms of ferroptosis: core regulatory pathways

2.1 Regulatory association between iron metabolism imbalance and ferroptosis

Iron, an essential element for living organisms, serves as a crucial trace element in numerous biochemical reactions and plays a central role in fundamental physiological processes such as DNA synthesis, oxygen transport, and cellular energy production. Cellular iron homeostasis generally depends on the coordinated regulation of iron uptake, export, and utilization. Disruption of iron metabolism can lead to excessive intracellular iron accumulation, which promotes the generation of ROS, causing damage to cells, tissues, and organs, and potentially triggering a unique form of regulated cell death known as ferroptosis.

Physiologically, Fe³⁺-bound transferrin (TF) is internalized via transferrin receptor 1 (TFR1), reduced to Fe²⁺ and transported by divalent metal transporter 1 (DMT1) into the labile iron pool (LIP) or ferritin (13–16). LIP saturation releases free Fe²⁺ to trigger Fenton reaction, ROS production, LPO and ferroptosis; excess iron is stored or exported via ferroportin (FPN) (17–19). Encoded by SLC40A1, FPN is the only mammalian iron exporter that oxidizes Fe²⁺ to Fe³⁺, maintaining systemic iron homeostasis and regulating ferroptosis (20, 21). This sophisticated transport system effectively balances iron utilization and storage while preventing iron-mediated oxidative damage (Figure 1).

Figure 1

Figure 1. Metabolic substrate regulation mechanisms of ferroptosis. At the iron substrate level, transferrin (TF) - transferrin receptor 1 (TFR1) - mediated iron uptake and ferritinophagy - released Fe²⁺ form the labile iron pool (LIP), and Fe²⁺ generates reactive oxygen species (ROS) via the Fenton reaction. At the lipid substrate level, acyl-coA synthetase long-chain family member 4 (ACSL4) mediates the lipidation of polyunsaturated fatty acids (PUFAs), and enzymes such as lipoxygenase (LOX) promote the peroxidation of phospholipid - bound PUFAs. Meanwhile, the Hippo/YAP and p53 pathways regulate TFR and ACSL4 - related molecules. Ultimately, under the imbalance of metabolic substrate homeostasis, the accumulation of lipid peroxidation induces ferroptosis.

Iron metabolism regulates ferroptosis mainly via LIP modulation (22). Studies indicate that suppressing ferritin expression elevates intracellular LIP levels and enhances cellular susceptibility to ferroptosis. Conversely, iron chelators or ferritin and its derivatives can significantly inhibit ferroptosis by either reducing intracellular iron levels or suppressing the activity of iron-containing metalloenzymes that catalyze lipid peroxidation (23, 24). Regulation of iron uptake represents a key mechanism for maintaining intracellular iron pool capacity. Iron ions enter cells via the TF/TFR1 system or the SLC39A14 channel. Upregulation of these transporters or hyperactivation of TFRC (the gene encoding TFR1) can induce intracellular iron overload, thereby promoting ferroptosis to varying degrees (25). Notably, heat shock protein β-1 (HSPB1) inhibits TFR1, reduces iron uptake, and maintains iron pool homeostasis (26–28). Additionally, iron-responsive element-binding protein 2 (IREB2), the central post-transcriptional regulator of iron metabolism, represses ferritin synthesis, boosts TFR1 expression, and simultaneously suppresses the iron exporter FPN1. This triple action dismantles iron sequestration, promotes iron uptake, and curtails iron efflux, raising cytosolic free Fe²⁺ and supplying the critical iron pool for ferroptosis.

Furthermore, heme oxygenase-1 (HO-1) critically regulates iron metabolism (29). Sustained HO-1 expression in non-erythroid cells perturbs iron homeostasis to mediate adaptive responses, and pro/anti-inflammatory signals modulate HO-1/iron exporter expression to control local iron levels in tissues (30, 31). Elevated HO-1 correlates with reduced ferroportin and increased ZIP14/pro-hepcidin, altering ferritin expression, inducing oxidative stress and suppressing proliferation (32). Notably, the HIF-2α/IRP1 axis coordinately regulates iron metabolism genes and ferroptosis-sensitizing factors (33). HIF-2α upregulates iron/lipid metabolism genes to enhance ferroptosis sensitivity, promoting iron-dependent ROS production and cysteine oxidation-induced death. IRP1 facilitates ferroptosis by maintaining iron homeostasis and regulating TFRC, FPN, FTH1 (34).

Iron plays an essential physiological role in the visual process. It helps maintain the antioxidant balance of retinal tissue by assisting in the clearance of free radicals, thereby protecting retinal structures from oxidative stress damage. However, disordered iron metabolism can lead to abnormal iron deposition and trigger lipid peroxidation, a mechanism that may be closely associated with the pathological progression of DR (35, 36).

2.2 Ferroptosis mechanisms mediated by lipid metabolism disorders

Lipid peroxidation stands as one of the core mechanisms driving ferroptosis. The lipid metabolism pathway—encompassing lipid synthesis, degradation, storage, conversion, and utilization—serves as a key regulator of cellular sensitivity or tolerance to ferroptosis. Cellular and organelle membranes are enriched with polyunsaturated fatty acids (PUFAs), which act as primary substrates for lipid peroxidation (37). Notably, both the concentration and intracellular distribution of PUFAs directly influence the extent of lipid peroxidation. The chemically reactive carbon-carbon double bonds in PUFAs enable their esterification into membrane phospholipids, followed by subsequent oxidation; this cascade of reactions ultimately propagates ferroptosis signals (38).

During lipid remodeling, two core enzymes—acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3)—drive PUFA-dependent ferroptosis (39). ACSL4 expression levels directly determine the concentration of specific lipid peroxides and indirectly modulate cellular susceptibility to ferroptosis. Phosphatidylethanolamine-binding protein 1 (PEBP1) is another critical regulator of lipid peroxidation. Knockdown of ACSL4, LPCAT3, or PEBP1 suppresses PUFA synthesis and inhibits ferroptosis (40). Multiple studies have confirmed a positive correlation between ACSL4 expression and cellular sensitivity to ferroptosis (37, 41, 42). Thus, downregulating ACSL4 expression may represent a key strategy for reducing cellular susceptibility to ferroptosis. Lipoxygenases (LOXs) are widely recognized as central regulators of lipid peroxidation and ferroptosis. All LOX isoforms promote PUFA peroxidation, and their knockdown has been consistently shown to attenuate ferroptosis (43). As previously noted, PEBP1 interacts with 15-LOX to guide the oxidation of membrane-bound PUFAs, further amplifying ferroptosis. This discovery further enriches the theoretical framework underlying lipid peroxidation in ferroptosis. High glucose suppresses retinal hepcidin, causing iron overload. Free iron fuels Fenton chemistry to generate ROS that assault polyunsaturated fatty acids and ignite lipid peroxidation. LOX is up-regulated, hydroperoxide removal is blocked, and retinal cells undergo ferroptosis. Lipid dyshomeostasis produces lipid droplets that further trap iron, completing a vicious cycle.

As essential components of cell membranes, PUFAs further play a pivotal role in regulating retinal lipid metabolism and exerting antioxidant effects. Such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are indispensable for visual development and retinal function. DHA is the most abundant omega-3 fatty acid in retinal photoreceptor cells, where it is essential for maintaining structural integrity and normal physiological function. EPA, meanwhile, mitigates inflammatory responses and reduces the risk of ocular diseases such as diabetic retinopathy degeneration. Furthermore, omega-3 PUFAs protect retinal tissues by alleviating oxidative damage through their intrinsic antioxidant mechanisms (44, 45).

Beyond PUFAs that chiefly tune ferroptosis via lipid peroxidation, dysregulated metabolism of other lipid species can also directly or indirectly modulate ferroptosis. For instance, sterol lipids (including cholesterol) can undergo oxidation within cell membranes or low-density lipoprotein (LDL) particles; cholesteryl esters, a derivative of cholesterol, are also susceptible to oxidation by LOXs (46, 47). These observations suggest a potential link between cholesterol oxidation and ferroptosis. Inner BRB breakdown lets lipoproteins leak into retina, raising retinal cholesterol, while the outer BRB—retinal pigment epithelium (RPE)—transports cholesterol from choroid. Retinal cholesterol arises from local synthesis or RPE uptake of choroidal lipoproteins. Disturbed cholesterol metabolism spurs sphingolipid accumulation, down-regulates SLC7A11, curbs glutathione (GSH) synthesis and sensitizes retinal cells to ferroptosis. Thus, diabetic cholesterol dyshomeostasis—inner BRB leak plus reduced conversion to soluble oxysterols by RPE and neuroretina—elevates retinal cholesterol and drives DR (48–52). Injecting heavily oxidized/glycated LDL reproduces human DR features: vascular leakage, ERG dysfunction, vascular endothelial growth factor (VEGF) overexpression, inflammation, ER stress and apoptosis (48, 53). Cholesterol is the end product of the mevalonate pathway, and other intermediates of this pathway—particularly squalene—may also regulate ferroptosis (54). Previous studies have demonstrated that squalene acts as an effective oxygen scavenger, inhibiting the propagation of free radical reactions (55). However, it is noteworthy that squalene is typically undetectable in human cell lines, and its protective effects may only be observed under specific experimental conditions or at high concentrations (56). Dysregulation of ceramide metabolism in the diabetic retina is well documented in vivo and in vitro (57–59).Tight junctions (TJs) seal the BRB; once they break, permeability skyrockets. Lipid control of TJ integrity has been postulated for decades but remains sketchy (60, 61). Free fatty acids (FFAs) are validated diabetic threats that tilt redox balance, raise ROS and cripple endothelium (62). Palmitate (PA), the most abundant saturated FFA, triggers oxidative damage in retinal ganglion cells and fuels DR (63). PA drives Keap1 palmitoylation in human retinal microvascular endothelial cells (HRMECs); si-Keap1 reverses the ensuing Keap1/ACSL4 surge, MDA-ROS rise, Nrf2-GPX4 and GSH drop, and lessens DR and ferroptosis in mice (64). Thus, PA magnifies ferroptosis via a palmitoylation-Keap1-Nrf2/GPX4 axis, offering a new metabolic-epigenetic cross-talk route in hyperglycaemic retinal injury.

Conversely, higher plasma monounsaturated FAs (MUFAs) track with better insulin sensitivity and lower diabetes risk (65). Multi-model lipidomics first show seven MUFAs inversely relate to DR, with oleic acid (OA) the top contributor. OA curbs high-glucose-driven TLR4-MCP-1 signaling, cuts VEGF output and calms retinal inflammation (66). However, PDR patients show even higher plasma OA. This suggests that OA has dual roles depending on dose and context. Single-omics or single-model studies cannot fully reveal its nature (67).

2.3 Interactive regulation between amino acid metabolic pathways and ferroptosis

Amino acid metabolism supplies essential biomolecules for human physiological functions, including proteins, energy substrates, glutathione, and neurotransmitters. The amino acid-based antioxidant system primarily modulates ferroptosis via the Xc^- system/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis (68). Ferroptosis is triggered by the excessive accumulation of lipid peroxides, which impair membrane integrity and ultimately result in cell lysis and death. GSH and its dependent enzyme, GPX4, are core molecules that reduce lipid peroxides and safeguard cells against ferroptosis. Intracellular free cysteine levels directly dictate GSH biosynthetic capacity. Thus, cysteine modulates ferroptosis by regulating GSH production (69).

The Xc^- system is a heterodimeric amino acid antiporter localized on the cell membrane, consisting of two subunits—SLC7A11 and SLC3A2—linked by a disulfide bond. This system mediates the exchange of extracellular cystine for intracellular glutamate. Incoming cystine is subsequently converted to cysteine, which serves as a substrate for GSH synthesis (70). Beyond supporting GSH biosynthesis, this cysteine also activates the mammalian target of rapamycin complex 1 (mTORC1) and upregulates GPX4 protein synthesis through the Rag–mTORC1–4EBP signaling axis. Under cystine deprivation, mTORC1 activity is inhibited, leading to reduced GPX4 protein levels and thereby enhancing cellular sensitivity to ferroptosis (71).

As a member of the glutathione peroxidase family, GPX4 is the first identified core suppressor of ferroptosis (Figure 2). It is the only selenoprotein capable of catalyzing the reduction of oxidized biological lipids (72). Inhibition of GPX4 activity abrogates the clearance of accumulated lipid peroxides and mitigates their cytotoxic effects, ultimately inducing ferroptosis (73). Currently, it is well established that cells counteract ferroptosis primarily through two parallel mechanisms centered on GPX4 or ferroptosis-suppressor protein 1 (FSP1). In this process, GSH acts as an essential substrate for GPX4, facilitating its reductive reactions and protecting cells from oxidative injury (74–76). Consequently, inhibition of GSH synthesis, impairment of GPX4 function, or certain pathophysiological conditions can all trigger ferroptosis. Inhibition of Xc^--mediated cystine uptake, which impairs GSH synthesis, is the primary mechanism of erastin-induced ferroptosis. Erastin indirectly inactivates GPX4, impairs cellular antioxidant defense, and causes cytoplasmic lipid ROS accumulation, thereby triggering ferroptosis (77). GPX4 plays a critical role in protecting retinal cells against oxidative stress and ferroptosis-associated damage (78). By catalyzing the GSH-dependent reduction of lipid peroxides, it aids in preserving cell membrane integrity against oxidative injury—an essential process for maintaining retinal homeostasis (79). In DR, downregulation of GPX4 may exacerbate oxidative stress and compromise the function and survival of retinal photoreceptor cells (80, 81).

Figure 2

Figure 2. Core inhibitory mechanisms of ferroptosis. The core inhibitory mechanisms of ferroptosis center on the regulation of lipid peroxidation. System Xc^- mediates cystine uptake and its metabolism into glutathione (GSH), and glutathione peroxidase 4 (GPX4) relies on GSH to clear peroxides of polyunsaturated fatty acids (PUFAs). Ferroptosis suppressor protein 1 (FSP1), the gtp cyclohydrolase 1-tetrahydrobiopterin-coenzyme Q (GCH1 - BH4 – CoQ) system, and mitochondrial dihydroorotate dehydrogenase (DHODH) can also inhibit lipid peroxidation. Nuclear factor erythroid 2-related factor 2 (NRF2) enhances the inhibitory effect by transcriptionally regulating molecules such as solute carrier family 7 member (SLC7A11) and GPX4, while p53 inhibits SLC7A11 to weaken this pathway. Erastin and RSL3 target SLC7A11 and GPX4, respectively, to block the inhibitory effect, and ultimately, the accumulation of lipid peroxidation induces ferroptosis.

Unlike erastin, RSL3—another classical ferroptosis inducer—does not act via GSH depletion. Instead, it binds covalently to the selenocysteine active site of GPX4, inactivating the enzyme and triggering lipid ROS accumulation (82–84). Thus, even under normal cysteine and GSH levels, direct inhibition of GPX4 can induce ferroptosis. In summary, GPX4 acts as a central regulator of ferroptosis, and the GSH antioxidant system plays a pivotal role in GPX4-mediated ferroptosis regulation. Notably, while most studies indicate that cysteine modulates ferroptosis via its role in GSH synthesis, inhibiting GSH synthesis alone is insufficient to induce ferroptosis—suggesting that cysteine may also regulate this process through alternative metabolic pathways (85). Beyond amino acids involved in GSH and GPX4 biosynthesis, additional amino acids are linked to ferroptosis. Studies have demonstrated that in experiments involving the deprivation of 14 distinct amino acids, the absence of glutamine, lysine, valine, methionine, and arginine inhibited erastin2-induced ferroptosis, whereas deprivation of glycine, tryptophan, phenylalanine, and serine had no significant impact (86–88).

Metabolomic profiling reveals that serum metabolites with significant differential expression between DR and NDR cohorts are predominantly amino acids, underscoring amino acid metabolic perturbation as a core DR-associated pathophysiological event that offers novel insights into disease pathogenesis (89). Retinal iron overload in the DR microenvironment elicits excessive production of ROS. On one hand, ROS-mediated damage to the cystine-glutamate antiporter SLC7A11—expressed on RMECs, RPE cells, and Müller cells—impairs cystine-cysteine biotransformation, disrupts the GSH- GPX4 antioxidant axis, and thereby triggers ferroptosis in these cell populations. Ferroptotic injury subsequently compromises BRB integrity, exacerbates iron accumulation and lipofuscin deposition, and culminates in retinal nerve fiber layer thinning and visual dysfunction. On the other hand, ROS downregulate taurine transporter (TAUT) expression, activate the mTOR signaling pathway in RMECs and Müller cells, and induce branched-chain amino acid (BCAA) metabolic imbalance. These perturbations synergistically attenuate cellular antioxidant capacity, promote iron retention, and amplify chronic retinal inflammation. Furthermore, iron overload upregulates arginase I in RMECs, accelerating arginine catabolism, reducing nitric oxide (NO) biosynthesis, and suppressing FPN1-mediated iron efflux to form a self-reinforcing vicious cycle (90–97). Key alterations in amino acid content and interconversion are summarized in Table 1.

Table 1

Table 1. Key alterations in amino-acid levels and interconversion under diabetic retinopathy conditions.

2.4 Coenzyme Q-dependent ferroptosis inhibitory pathways

2.4.1 Molecular mechanism of FSP1-CoQ10-NADPH pathway in regulating ferroptosis

Ubiquinone (CoQ), a class of redox-active lipid molecules, plays a core regulatory role in maintaining intracellular homeostasis. FSP1 belongs to the family of glutathione-independent ferroptosis-regulating proteins (98–101). This protein can effectively counteract the ferroptotic process caused by the deficiency of GPx4 expression. Furthermore, FSP1 can mediate the regeneration cycle of CoQ10 relying on NADPH, thereby forming a functional synergy with the GPx4-glutathione antioxidant system (102). GPx4 dysfunction rapidly activates the FSP1-CoQ10-NADPH pathway.

Bersuker’s team confirmed that the core function of FSP1 is tightly linked to its myristoylation modification. This post-translational modification enables FSP1 to assemble into plasma and endoplasmic reticulum membranes, and myristoylation site mutations or aberrant modification markedly impair its ferroptosis-inhibiting activity. In vitro assays demonstrated that FSP1-knockout cells show heightened sensitivity to GPx4 inhibitors, further validating FSP1 as a key component of the ferroptosis defense system (103). In addition, study demonstrated that FSP1-knockout mice survive normally with no obvious phenotypes, consistent with GPx4’s compensatory lipid peroxidation inhibition, indicating functional complementarity between FSP1 and GPx4 (104). In summary, FSP1-CoQ10-NADPH forms an independent parallel defense system, complementing the classical glutathione-GPX4 pathway to inhibit phospholipid peroxidation and block ferroptosis.

In the physiological process of retinal injury repair, FSP1 also exerts a key regulatory function. This protein can provide core driving force for the repair and healing of damaged ocular tissues by upregulating the expression levels of cell adhesion molecules such as the integrin family and enhancing cell migration activity. It maintains RPE cells polarity via cytoskeletal regulation, participates in ZO-1/Claudin-1 synthesis to preserve RPE integrity and retinal function. In ocular neovascular diseases, FSP1 modulates vascular endothelial cell proliferation/differentiation/migration to regulate pathological neovascularization and scar formation (105). In addition, in the pathological progression of DR, FSP1 targets retinal inflammation and fibrous scar deposition (106). FSP1’s transcellular multi-pathway regulatory network confirms its core role in ferroptosis defense and multifaceted regulation of ferroptosis pathological sensitivity, providing theoretical support for DR pathogenesis research and therapeutic target screening.

2.4.2 Mitochondrial ferroptosis defense mechanism mediated by DHODH-CoQH2 pathway

Dihydroorotate dehydrogenase (DHODH), as the key rate-limiting enzyme in the pyrimidine nucleotide synthesis pathway, not only participates in nucleic acid metabolism but also catalyzes the reduction of CoQ10 to reduced coenzyme Q10 (CoQ10H2) on the inner mitochondrial membrane, thereby exerting antioxidant function (107). Studies have shown that DHODH, GPX4 and FSP1 form three major cellular protective systems with coordinated defense via distinct subcellular localizations (108). In mitochondrial ferroptosis defense, DHODH and mitochondrial GPX4 functionally complement: DHODH blocks lipid peroxidation initiation by sustaining CoQ10H₂ production, and GPX4 scavenges lipid peroxides to maintain mitochondrial membrane stability. Acute mitochondrial GPX4 inactivation upregulates DHODH metabolic flux, accelerating CoQ10H₂ synthesis to neutralize lipid radicals, compensate for GPX4 deficiency and inhibit mitochondrial inner membrane ferroptosis (109). Notably, GPX4 or FSP1 cannot substitute for the protective role of DHODH, highlighting the uniqueness of the mitochondrial localized defense system. Studies demonstrated that type I interferon enhances manganese-induced ferroptosis sensitivity by downregulating mitochondrial DHODH, elucidating the underlying molecular mechanism. Consistently, the DHODH inhibitor Brequinar specifically promotes ferroptosis in GPX4-low-expressing cells by reducing mitochondrial CoQ10H₂ levels (110). The DHODH-mediated ferroptosis defense mechanism not only deepens the understanding of the association between pyrimidine metabolism and cellular redox homeostasis but also provides experimental basis for targeting mitochondrial antioxidant systems in disease treatment, and exhibits potential value in intervening GPX4 deficiency-related diseases.

2.4.3 Regulatory role of GCH1-BH4-CoQ10 pathway in ferroptosis

Guanosine triphosphate cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the synthesis of tetrahydrobiopterin (BH4) and also acts as an alternative pathway for inhibiting ferroptosis that is independent of the GPx4-GSH cysteine axis (111). Studies have shown that the GCH1/BH4 axis plays a crucial role in ferroptosis, and this role is independent of the GSH/GPX4, FSP1/CoQ10, and DHODH/CoQH2 axes (112). Photoreceptor cells are prone to oxidative damage. Relevant studies have shown that GCH1 activity in the retina is crucial for protecting photoreceptor cells from light-induced damage (113). However, the molecular targets of BH4-mediated direct antioxidant effect remain undefined, and specific research in the hyperglycemic and hypoxic pathological microenvironment of DR is lacking, with the heterogeneous role of BH4 in retinal cells yet to be further elucidated.

2.5 Core role of mitochondrial dysfunction in ferroptosis

In recent years, a growing body of research has revealed that mitochondria play a key regulatory role in the occurrence and development of ferroptosis (114, 115). Voltage-dependent anion channels (VDACs), core mitochondrial membrane proteins, mediate iron/fatty acid transmembrane transport, regulate cyto-mitochondrial iron homeostasis via iron metabolism-related protein interaction and participate in ROS generation (116). High VDAC-expressing RAS-mutant cells are more sensitive to erastin. VDAC2/3 knockdown inhibits erastin-induced ferroptosis, and erastin directly binds VDAC2 (117). VDAC opening mediates the entry of most metabolites into mitochondria, promoting mitochondrial oxidative phosphorylation and ROS production, and ultimately leading to mitochondrial dysfunction. Mitochondrial metabolic dysfunction reduces GSH production, impairs GPx4-mediated LPO clearance, and predisposes cells to ferroptosis (118). A study found that erastin-induced ferroptosis reduces glycolytic flux, associated with increased ATP synthesis and oxidative phosphorylation (119).

ROS generation and accumulation are key nodes in mitochondrial regulation of ferroptosis. Iron homeostasis imbalance elevates ROS levels, which degrade mitochondrial membrane-associated enzymes, impair mitochondrial membrane structure, and reduce mitochondrial membrane potential (3). Mitochondrial iron ions bind to sulfhydryl groups to generate free radicals, exacerbating oxidative stress, impairing mitochondrial membrane and enzyme function, and ultimately inducing cell death. In DR, high glucose-induced mitochondrial iron metabolic disorder and excessive ROS production synergistically activate retinal cell ferroptosis. Excess ROS impairs mitochondrial iron metabolic homeostasis, amplifies the Fenton reaction, exacerbates mitochondrial membrane damage and lipid peroxidation accumulation, thereby triggering retinal cell ferroptosis and accelerating BRB disruption as well as the pathological progression of DR. Studies have found that inducing mitochondrial oxidative stress in microglia can trigger ferroptosis, characterized by increased iron content in mitochondria, enhanced ROS production, and elevated lipid peroxidation levels (120). Mitochondria - targeted ROS scavengers can maintain the structural integrity and function of mitochondria, thereby resisting cellular ferroptosis (121).

Mitochondria and Ca²⁺ are tightly coupled to tune multiple metabolic events, and Ca²⁺ fluctuations modulate ferroptosis by reshaping mitochondrial function (122). Recent work shows that blocking mitochondrial ROS or curbing Ca²⁺ influx protects cells against Xc^--inhibitor-induced ferroptosis (123, 124). Ca²⁺ overload also activates calcineurin and other signaling molecules, thereby regulating VDAC channel activity and iron-metabolism gene expression to indirectly influence ferroptosis. However, whether Ca²⁺ drives DR-related ferroptosis via mitochondrial pathways remains largely unexplored and warrants deeper investigation.

2.6 Other key regulatory pathways of ferroptosis

2.6.1 Nrf2 pathway-mediated antioxidant regulation of ferroptosis

As the core transcription factor for cellular antioxidant stress, Nrf2 regulates ferroptosis via multiple pathways (125). On one hand, Nrf2 activates downstream target genes to regulate iron metabolism-related genes, reducing intracellular free iron accumulation and Fenton reaction-induced oxidative damage (126–130). It upregulates GSH synthetic key enzymes and GPx4 expression, strengthening cellular LPO scavenging capacity and blocking ferroptosis (131, 132). On the other hand, oxidative stress signals reversely activate the Nrf2 pathway. ROS mediate Keap1 conformational change, relieving its inhibition on Nrf2 and enabling Nrf2 nuclear translocation to exert antioxidant defense (133).

In DR, high glucose inhibits Nrf2 activity by activating protein kinase C (PKC) and accumulating advanced glycation end products (AGEs), reducing retinal cell GSH/GPx4 levels, impairing iron export, inducing free iron and LPO accumulation, and activating ferroptosis in Müller, ARPE and endothelial cells, exacerbating vascular leakage (134–136). Therefore, activating retinal Nrf2 pathway to restore iron metabolism and lipid peroxidation regulation is a potential strategy for delaying DR progression. However, the core downstream target genes mediating Nrf2-regulated DR iron metabolism and lipid peroxidation lack in-depth validation, and the optimal activation strategy, long-term safety of Nrf2 pathway and its crosstalk with other ferroptosis regulatory pathways remain insufficiently studied, warranting further investigation.

2.6.2 Regulatory role of p53 pathway in ferroptosis

p53 acts as a transcriptional repressor of SLC7A11, inhibiting cysteine uptake to promote ferroptosis (137–139). Studies show negative correlation between p53 activation and SLC7A11 expression in mouse embryonic fibroblasts (MEFs), confirming this regulatory relationship (140).

Furthermore, p53 induces SAT1 transcription to promote lipid peroxidation and ROS-dependent ferroptosis, and iron depletion upregulates SAT1 expression (141). Glutamine metabolism regulates ferroptosis: glutaminase 2 (GLS2) is a novel p53 target, and p53 promotes ferroptosis by activating GLS2 (142). It is worth noting that the regulation of ferroptosis by p53 is bidirectional. One study found that p53 promotes DPP4 nuclear translocation to form complexes, inhibiting NOX-mediated lipid peroxidation and ferroptosis; p53 deficiency allows DPP4 to bind NOX1, exacerbating lipid peroxidation and ferroptosis. This indicates p53 may also negatively regulate ferroptosis (143, 144). Currently, the subtype-specific regulation of retinal target cells by p53 under high glucose remains undefined, and the switch mechanism of p53 bidirectional ferroptosis regulation is unclarified, warranting further research on its specific mechanisms.

2.6.3 Association mechanism between NADPH metabolic imbalance and ferroptosis

Nicotinamide adenine dinucleotide phosphate (NADPH), is closely associated with the pathogenesis and progression of various metabolic diseases, and plays a pivotal role in ferroptosis regulation by modulating antioxidant system function and iron metabolism homeostasis, with its intracellular levels directly dictating cellular susceptibility to ferroptosis (145, 146). The pentose phosphate pathway (PPP) is a major source of cytoplasmic NADPH, with glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) as core rate-limiting enzymes (147). Studies have found that knocking down G6PD or 6PGD significantly inhibits erastin-induced ferroptosis, suggesting PPP-derived NADPH participates in ferroptosis occurrence (148).

In fundus diseases, NADPH regulates ferroptosis to modulate pathological progression (149). DR retinal chronic inflammation amplifies RPE ferroptosis: inflammatory factors activate NOX to produce ROS via NADPH, damaging antioxidant systems and inducing ferritinophagy to release free Fe²⁺, further enhancing ferroptosis signals (150). Current research has confirmed that supplementing NADPH precursors, iron chelators, or inhibiting NOX activity effectively alleviates ferroptosis of DR. Targeting the NADPH metabolic pathway is a promising therapeutic strategy for DR. However, the optimal dosage, administration route and long-term safety of NADPH precursors remain unvalidated in large animal models, and the crosstalk of NADPH metabolism, iron homeostasis and retinal inflammation is poorly understood, limiting clinical translation of NADPH-targeted therapies and requiring further investigation.

3 Synergistic pathogenic mechanisms of ferroptosis in DR

3.1 Vicious cycle mechanism of oxidative stress-BRB injury-ferroptosis

Oxidative stress is defined as an imbalance between reactive oxygen species (ROS) and the endogenous antioxidant defense system, and the retinal tissue and cellular damage it mediates serves as a core pathological driver of diabetic retinopathy (DR) progression (151). Diabetic patients present with chronic hyperglycemia, and elevated glucose levels together with canonical hyperglycemia-associated metabolic pathways (polyol pathway, hexosamine pathway, protein kinase C activation, and advanced glycation end product accumulation) induce excessive ROS production to trigger oxidative stress (152–155). Excessive ROS not only directly causes oxidative damage to retinal cells and initiates retinal neovascularization, but also impairs the structural and functional integrity of the BRB. BRB disruption is a primary pathogenic mechanism of DR and the key factor driving DR progression from non-proliferative DR (NPDR) to proliferative DR (PDR). Under physiological conditions, the BRB coordinates vascular and extravascular systems to maintain osmotic balance, regulate ion concentrations, and facilitate nutrient/metabolite transport, thereby preserving retinal microenvironmental homeostasis. Retinal ischemia-hypoxia induced by BRB impairment further triggers neovascularization and nonperfusion, which exacerbates oxidative stress dysregulation and iron metabolism imbalance, forming a vicious positive feedback loop between oxidative stress and BRB damage that accelerates DR pathogenesis and amplifies ferroptosis susceptibility via iron overload and lipid peroxidation.

Cells harbor an endogenous antioxidant system comprising superoxide dismutase (SOD) and catalase: SOD converts superoxide anions to H₂O₂, and catalase further reduces H₂O₂ to water. In diabetes, retinal antioxidant defense enzyme activity is impaired, leading to excessive free radical accumulation (156). Hyperglycemia acts as both an initiator of oxidative stress and a co-promoter of pathogenic molecular pathways, and cross-talk among these pathways induces ROS amplification via positive feedback, exacerbating oxidative damage, BRB impairment, iron dyshomeostasis and DR progression (157, 158). Pharmacological alleviation of oxidative stress effectively ameliorates DR pathology, validating oxidative damage clearance as a promising therapeutic strategy for DR.

Ferroptosis, an oxidative stress-dependent regulated cell death modality, is potently triggered by oxidative stress, a mechanism particularly critical in ocular pathologies (159).Accumulating evidence implicates ferroptosis in retinal neurodegeneration and DR pathogenesis, supporting oxidative stress as a central bridge linking ferroptosis to DR progression (160, 161). Notably, ROS scavenging by N-acetylcysteine (NAC) inhibits high-glucose-induced ferroptosis, confirming that oxidative stress-mediated ferroptosis contributes to DR pathogenesis (162). A novel miR-338-3p/SLC1A5 axis has been identified as a key regulator of oxidative stress-induced ferroptosis in DR: high glucose significantly upregulates miR-338-3p expression in RPE cells, and miR-338-3p silencing reverses RPE cell death and ferroptosis (9). Mechanistically, hyperglycemia-induced miR-338-3p upregulation represses SLC1A5 expression, thereby impairing antioxidant capacity and triggering oxidative stress-mediated ferroptosis, which in turn exacerbates BRB damage and oxidative stress to form a oxidative stress-BRB impairment-ferroptosis positive feedback loop that drives DR progression. Additionally, as aROS-derived lipid, 4-hydroxynonenal (4-HNE) serves as one of the core mediators driving the pathogenesis and progression of retinal pathology induced by systemic metabolic diseases. Studies have demonstrated that the levels of 4-HNE, p53 and phosphorylated p53 are significantly elevated, whereas the levels of GSH, SLC7A11 and GPX4 are decreased in both C57BL/6J mice and cultured HRECs (11).

Although studies have confirmed that the three components form a positive-feedback loop that drives DR progression and that antioxidant therapy can alleviate DR pathology, the key molecular triggers that initiate the loop—such as the cell-specific mechanisms by which hyperglycemia induces excessive ROS production in different retinal cells—remain poorly defined. Moreover, regulatory axes such as miR-338-3p/SLC1A5 have been examined almost exclusively in retinal pigment epithelial cells; whether they operate similarly in retinal endothelial cells, pericytes, or other retinal subpopulations has not been tested. Systematic data describing how this feedback loop evolves across DR stages (non-proliferative versus proliferative) are also lacking, making it difficult to align potential interventions with the precise windows of the clinical disease course.

3.2 Synergistic pathogenic mechanism of inflammation-neovascularization-ferroptosis

Iron overload acts as a pivotal hub linking ferroptosis, inflammatory responses, and pathological neovascularization in DR. These three pathological processes drive the progression of DR from the non-proliferative to the proliferative stage and induce retinal neurodegeneration through cascade amplification and positive feedback regulation. In a hyperglycemic microenvironment, iron overload promotes VEGF secretion through two synergistic pathways. First, it enhances succinate accumulation and upregulates its receptor GPR91, and the activated succinate/GPR91 axis triggers VEGF production via the ERK1/2, p38 MAPK, and JNK signaling pathways. Second, it induces oxidative stress, which further amplifies VEGF overexpression (163, 164). Excessive VEGF accelerates the degradation of tight junction proteins (ZO-1, claudin-5, occludin), increases the abundance of caveolae in the membranes of RECs, and directly disrupts the BRB, subsequently inducing retinal edema. Tripartite motif-containing 46 (TRIM46) exerts dual regulatory effects on RECs dysfunction and ferroptosis initiation. By promoting the ubiquitination and degradation of GPX4, and IκBα, TRIM46 not only triggers ferroptosis via catalyzing membrane lipid peroxidation but also activates inflammatory cytokine cascades. This process not only reduces transendothelial electrical resistance (TEER) and increases RECs permeability but also further downregulates the expression of ZO-1 and claudins through the nuclear factor-κB (NF-κB) pathway, resulting in a synergistic effect on BRB disruption (165).

In addition, oxidative stress and inflammation induced by iron overload impair the signal crosstalk between pericytes and RECs, leading to pericyte loss and the complete collapse of the BRB structure (166). In RPE cells, iron overload downregulates the expression of circSPECC1 and Rpe65, which disrupts RPE cells polarity, induces ultrastructural abnormalities and atrophy, and activates microglia. These pathological alterations ultimately damage the outer BRB and accelerate RPE cell death (167). Notably, overexpression of ubiquitin-specific protease 48 (USP48) can inhibit the above pathological processes by deubiquitinating SLC1A5, suggesting that targeting the ferroptosis-inflammation axis represents a promising potential strategy for DR treatment (168). However, significant gaps persist. First, no systematic profiling of key inflammatory cytokines has been performed, so the full regulatory map of the ferroptosis–inflammation–neovascularization axis remains sketchy: the exact spectrum of cytokines released upon iron overload and their divergent effects on ferroptosis versus neovascular signaling are still undefined. Second, the molecular details of how iron overload disrupts communication between pericytes and retinal endothelial cells are poorly understood, and therapeutic strategies aimed at this cooperative vulnerability remain confined to cellular and animal models, with no clinical data on efficacy or safety.

3.3 Bidirectional regulatory relationship between autophagy and ferroptosis

Autophagy is a lysosome dependent physiological process that maintains homeostasis by degrading damaged macromolecules or organelles within the cell. Although ferroptosis is a novel form of programmed cell death distinct from autophagy, the two are not isolated but rather form a bidirectional regulatory relationship through multiple molecular mechanisms. Both the initiation and progression of ferroptosis involve autophagy. Autophagy can degrade iron related proteins and antioxidant molecules to promote ferroptosis, but it can also clear peroxidized lipids and damaged organelles to inhibit ferroptosis. The specific regulatory direction depends on the cell type, the intensity of stress signals, and the microenvironment (169, 170).

In a high - glucose environment, autophagy can degrade toxic ferritin through ferritinophagy to release Fe²⁺, which produces ROS via the Fenton reaction, thereby amplifying ferroptosis driven by LPO (171, 172). On the other hand, it can also clear peroxidized lipids and damaged organelles, maintain the GSH/GPx4 system, and inhibit ferroptosis (173). Studies have found that in the retinal tissue of DR patients, high glucose can induce upregulation of NCOA4 expression, enhance ferritinophagy, reduce FtL, increase LC3-II/I, and activate NOX to produce ROS, forming a “ROS – ferritinophagy-free iron” positive feedback loop (172). BECN1 and ATG7 have been identified as potential biomarkers (174).Long-term high glucose can deplete autophagy-related proteins or inhibit flux through AGEs, weakening antioxidant protection and thereby exacerbating ferroptosis. Mitophagy can both clear damaged mitochondria to reduce ROS and promote ferroptosis by inhibiting complex I or upregulating HO-1 (175).

As previously mentioned, AMPK/mTOR regulates ferroptosis in DR (176). However, whether mTOR mediates ferroptosis and regulates Müller cells in DR remains unclear. Moreover, the regulation of both processes relies on common signaling pathways, further strengthening their association in DR. For example, the nuclear transcription factor Nrf2 is both a positive regulator of autophagy and a key inhibitor of ferroptosis (177). Current studies confirm that the two processes are linked via shared pathways such as ferritinophagy, mitophagy, and Nrf2, yet many questions remain. First, the net direction of autophagy’s effect on ferroptosis—pro-death or pro-survival—depends on cell type and stress intensity, but the dominant mode in each retinal cell population within the DR micro-environment is still unclear. Second, whether mTOR itself drives ferroptosis and governs Müller-cell function in DR has not been settled, and the molecular details of how the AMPK/mTOR axis steers their crosstalk are fragmentary. Finally, most reports examine only a single autophagy subtype or pathway; integrated analyses of how different autophagic routes cooperate or compete to tune ferroptosis are missing, and therapeutic strategies aimed at their common nodes still require rigorous pre-clinical validation of specificity and efficacy.

4 Ferroptosis in retinal cells

4.1 Regulatory mechanisms and pathological roles of ferroptosis in RPE cells

Retinal pigment epithelial (RPE) cells are located between the choroid and photoreceptors, undertaking core functions such as phagocytosis of photoreceptor outer segments, transport of nutrients, and inhibition of oxidative stress. They are key cells in maintaining retinal homeostasis, and their functional impairment or death is closely related to the progression of DR and other retinal diseases (178). An increasing number of studies have observed ferroptosis in both in vivo and in vitro models of DR (179, 180). The key mechanisms of ferroptosis are closely related to the pathological mechanisms of DR, including iron homeostasis imbalance, lipid peroxidation, glutathione depletion, GPX4 inactivation, and LOX upregulation (Figure 3). Under normal conditions, the intracellular antioxidant system can clear excess ROS. However, in patients with DR, the activity of the antioxidant system is reduced, leading to a surge in ROS production. This is both the main cause of the phenomenon triggered by hyperglycemia and the core inducer of the decline in RPE cell vitality and function (168, 181, 182). High glucose activates the PKC pathway and promotes the accumulation of advanced glycation end products (AGEs), which on the one hand accelerates the consumption of NADPH in RPE cells. The depletion of NADPH directly leads to a decrease in GSH levels, inactivates GPx4, and prevents the clearance of intracellular LPO, eventually causing the accumulation of LPO. On the other hand, AGEs bind to the RAGE on the RPE cell membrane, disrupting iron metabolic homeostasis and accelerating the ferroptosis process in RPE cells (183–185). It has been found that treating RPE cells with high-concentration glucose solution (30 mM) increases ROS levels, promotes cell ferroptosis, and inhibits cell proliferation and vitality in RPE. However, co-treatment of cells with the ferroptosis inhibitor Ferrostatin-1 and NAC can reverse ferroptosis (9). Tang et al. found that high glucose promotes the death of ARPE-19 RPE cells, increases the levels of ROS and oxidized glutathione (GSSG), and enhances the lipid peroxidation density of the mitochondrial membrane. Adding Fer-1 to RPE cells reduces cell mortality, indicating that HG-induced oxidative damage occurs due to ferroptosis (186). Ferroptosis drives the further occurrence and development of DR through lethal ROS accumulation, iron overload, and uncontrolled lipid peroxidation, leading to RPE cell damage and death. In addition, it has been found that the miR-338-3p/SLC1A5 axis plays a key regulatory role in this process. Both knockout of miR-338-3p and overexpression of SLC1A5 can eliminate ferroptosis caused by high glucose in RPE cells (9).

Figure 3

Figure 3. Potential mechanisms of ferroptosis in diabetic retinopathy. Hyperglycemia and hypoxia, as core microenvironmental stimuli in diabetic retinopathy (DR), trigger ferroptosis in retinal cells through multiple pathways: activating the hypoxia-inducible factor-1α (HIF - 1α) pathway to upregulate vascular endothelial growth factor (VEGF), which induces vascular leakage/neovascularization, while also activating the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway to promote Polyunsaturated fatty acids (PUFA) accumulation and inhibit autophagy to weaken reactive oxygen species (ROS) clearance; hypoxia also disrupts iron homeostasis by upregulating transferrin receptor 1 (TFR1)/divalent metal transporter 1 (DMT1) and downregulating ferroportin 1 (FPN1), and inhibits System Xc^- (SLC7A11) to reduce glutathione (GSH) synthesis; excessive Fe²⁺ synergizes with PUFAs to induce lipid peroxidation (LPO), ultimately leading to ferroptosis. ROS bidirectionally regulates ferroptosis: the p53 pathway exacerbates it, while the adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway inhibits it, and ferroptosis in retinal cells directly drives the progression of DR by disrupting the blood - retinal barrier, microvasculature, and causing neuronal damage.

Nrf2, a key transcriptional regulator involved in redox homeostasis, plays a crucial role in antioxidant stress (187). Sirt1, a class III protein deacetylase, can promote the deacetylation of histone lysine residues and regulate the activity of various transcription factors such as PGC-1α, NF-κB, and P53 (188, 189). It has been found that a high-glucose environment reduces the expression levels of Sirt1 and Nrf2 in the nuclei of retinal pigment epithelial cells and inhibits the expression of downstream Nrf2 genes such as GPX4, GCLC, and GCLM (190).

Cofilin-2 (CFL2), as a member of the actin-binding protein family, is crucial for maintaining normal muscle function (191, 192). In recent years, more functions of CFL2 have been gradually revealed. In DR, CFL2 has been proven to be overexpressed in RPE cells induced by high glucose, and its upregulation exacerbates high glucose-induced cell ferroptosis (193). Specific protein 1 (SP1) is a sequence-specific DNA-binding protein that has been proven to regulate tumor proliferation, angiogenesis, and metastasis (194). This protein can bind to the promoter regions of multiple genes associated with the progression of diabetic retinopathy, such as ROBO1 and MALAT1 (195, 196). However, whether SP1 regulates CFL2 to mediate high glucose-induced RPE cell damage remains unknown. Although existing literature has clarified the core role of RPE cell ferroptosis in DR progression and preliminarily elucidated the regulatory mechanisms of iron homeostasis imbalance, lipid peroxidation and related molecular axes, multiple limitations remain. Most studies lack sufficient detection of ferroptosis-specific phenotypes, and in vivo research is deficient in the localization of RPE-specific ferroptosis, dynamic changes across distinct DR stages, and validation of targeted interventions.

4.2 Role and mechanism of müller cell ferroptosis in DR

During the progression of DR, Müller cells play a pivotal role. Studies have found that in the early stages of diabetic retinopathy, pathological changes occur in Müller cells prior to those in retinal vascular endothelial cells and pericytes (197). Early retinal pathological changes include the activation of retinal glial cells, with the most significant being the activation of Müller cells. Activated Müller cells can release a large number of inflammatory factors and cytokines, which disrupt the stable retinal microenvironment through various molecular pathways (198). An increasing number of viewpoints now suggest that diabetic retinopathy is not merely a vascular complication but rather a neurovascular disorder. Neuroinflammation and retinal neurodegeneration are early driving factors of DR (199, 200).

Müller cells, the main glial cells of the retina, are radially distributed throughout the entire retinal layer and are considered the structural and functional link between retinal neurons and the vitreous cavity, subretinal space, and blood. They are crucial for retinal homeostasis and highly sensitive to hyperglycemia (201). Under hyperglycemic conditions, Müller cells experience oxidative stress, inflammation, and mitochondrial dysfunction, leading to neuronal damage and neuroinflammation (202–205). Recent studies have shown that hyperglycemia disrupts the iron homeostasis of Müller cells, making them susceptible to ferroptosis, characterized by lipid peroxidation, iron overload, and impaired antioxidant defenses (206, 207). Studies have shown that glucose concentrations above 25 mM trigger ferroptosis, marked by increased levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and Fe²⁺, as well as altered expression of ACSL4, ALOX15, GPX4, and SLC7A11 (208, 209). Ferroptosis inhibitors can suppress lipid peroxidation, restore GPX4 expression, and enhance cell viability, while inducers exacerbate cell death (210, 211). These findings indicate that hyperglycemia induces Müller cell ferroptosis via iron overload, lipid peroxidation and Xc^-–GSH–GPX4 axis dysfunction, which further exacerbates neuroinflammation through microglial reactivation and impairs the BRB. Notably, these studies are still mostly based on cellular or animal models with unvalidated clinical translatability, and the cross-validation of ferroptosis regulatory mechanisms remains insufficient. AQP4 positively regulates TRPV4 expression. Overexpression of TRPV4 enhances ferroptosis and oxidative stress in Müller cells treated with high glucose, while inhibition of TRPV4 has a protective effect on retinal damage caused by DR in rats (212). TRPV4 may be a potential therapeutic target for DR.

4.3 Ferroptosis in RMECs and vascular function injury mechanisms

The retina is in a metabolically active state due to elevated oxygen consumption, high glucose utilization, and abundant levels of PUFAs. These biochemical characteristics make ocular neural tissues more susceptible to oxidative damage compared to the whole-body biological system. RMECs, as the basic structural units of the retinal microvasculature, are an important component of the inner BRB. Since capillary endothelial cell dysfunction and death are the initiating factors of diabetic retinopathy, timely and precise management of endothelial abnormalities may delay the progression of DR (213–217). Studies have shown that endothelial dysfunction caused by oxidative stress-mediated endothelial inflammation, lipid peroxidation, and activation of PCD is the root cause of these changes (218, 219). High concentrations of VEGF can induce structural and functional changes in human retinal microvascular endothelial cells (HRMECs), leading to pathological vascular remodeling, which in turn exacerbates vascular leakage and abnormal angiogenesis (220). Studies have found that berberine can effectively intervene in the course of DR by inhibiting ferroptosis in HRMECs, and its mechanism of action may be realized through the Nrf2/HO-1/GPX4 signaling pathway (221). Similarly, studies have shown that amygdalin treatment through the NRF2/ARE signaling pathway can significantly inhibit ferroptosis and oxidative stress in HRECs stimulated by high glucose (222). A study analyzing the association between ferroptosis and DR in vitreous samples from patients with PDR confirmed that high glucose-induced ferroptosis shows a time-dependent feature in HRMECs. The study found that high glucose-induced loss of PCBP1 activates the HIF-1α/HO-1 pathway, leading to intracellular iron homeostasis imbalance and increased ferrous ion levels, while also exacerbating lipid peroxidation and ferroptosis. Moreover, overexpression of PCBP1 or direct targeting of HO-1 can effectively alleviate iron overload, lipid peroxidation, and ferroptosis in HRMECs and improve cell viability by downregulating HO-1 expression (223). These findings suggest that enhancing PCBP1 activity may become a potential new direction for the treatment of DR. Other studies have shown that TRIM46 enhances lipid peroxidation and ferroptosis in HRCECs stimulated by high glucose through promoting GPX4 ubiquitination (178). Interestingly, a study found that reduced vitamin D plays a key role in the oxidative stress and vascular endothelial injury caused by diabetes. 25 (OH) D3 may inhibit ferroptosis in HRMVECs induced by high glucose by downregulating miR – 93 (224). However, compared with traditional markers such as inflammation and apoptosis, the emerging programmed-cell-death modality of ferroptosis has received little attention in diabetic endothelial dysfunction. Work to date concentrates on canonical pathways, leaving the core ferroptotic circuits, molecular targets and regulatory networks that drive retinal microvascular endothelial-cell (RMEC) injury undefined. Moreover, associations with routine clinical endocrine indices (e.g., HbA1c) are lacking, and the efficacy and translational value of ferroptosis-targeted interventions remain to be proven—critical gaps that now demand urgent attention.

5 Potential therapeutic strategies targeting ferroptosis

Research on the mechanisms of ferroptosis has opened up new avenues for the treatment of DR. (Table 2).

Table 2

Table 2. Mechanisms of ferroptosis - related targets in DR.

5.1 Therapeutic potential of ferroptosis inhibitors in DR

Fer-1 is a well-known specific small molecule ferroptosis inhibitor that can eliminate lipid peroxides. This drug has shown significant protective effects in various preclinical models, including retinal cells (232). These lipophilic antioxidants can eliminate lipid peroxide radicals and prevent the spread of lipid peroxidation reactions, thereby maintaining cell membrane integrity. In the streptozotocin (STZ)-induced diabetic rat model, intravitreal injection of the ferroptosis inhibitor Fer-1 significantly reduced retinal inflammation, maintained the integrity of BRB, and prevented RGCs loss, which was confirmed 4–8 weeks after diabetes induction (232, 233). Under high glucose conditions, in 661W cells and photoreceptor cells of diabetic mice, the expression of GPX4 and SLC7A11 is downregulated, while the expression of ACSL4, FTH1, and NCOA4 is upregulated. Fer - 1 can alleviate ferroptosis and protect the retina from light - induced retinal degeneration (232). In addition, it was found that Fer-1 can reduce cell damage and the accumulation of ferrous iron in HRECs treated with high glucose, and also improve mitochondrial membrane potential and restore GSH levels (179, 230). However, unfortunately, although in vitro and in vivo experiments have clarified Fer-1’s protective effect on the DR retina and its ferroptosis-regulating mechanism, corroborating the clinical potential of ferroptosis-targeted intervention, critical limitations remain in its targeting specificity, potential off-target risks and clinical translational potential of preclinical models. Insufficient in vivo stability of Fer-1 directly restricts its clinical translatability, pending further validation and optimization. Though defined as a specific ferroptosis inhibitor, Fer-1 is a blanket lipophilic antioxidant; it hits all retinal cells alike, lacks aimed action on DR-critical cells, and can blur normal redox signaling. Intravitreally, it may accumulate and turn toxic at high doses. Systemically, it risks upsetting whole-body iron homeostasis, adding off-target liability. Furthermore, the lack of large-sample long-term experimental data results in undefined efficacy and safety of Fer-1 for DR at different stages, further reducing the practical translational value of this agent.

5.2 Mechanism of iron chelators in improving DR by regulating iron homeostasis

Iron chelators are the main drugs for treating methemoglobinemia. They can chelate excess iron ions to reduce iron-catalyzed free radical reactions, thereby alleviating oxidative stress damage to retinal cells. Deferoxamine (DFO) can directly chelate iron elements and has been approved by the US Food and Drug Administration for clinical treatment to reduce the bioavailability of iron (234). An experimental study showed that in the mature genetic model of type 2 diabetes, the db/db mouse, after systemic administration of the iron chelator deferoxamine by intraperitoneal injection for 12 weeks, significant reductions in inflammatory markers such as IL-1β and TNF-α were observed, and retinal electrophysiological function was improved. At the same time, it can also increase the levels of antioxidants such as GPX4, GSH, and SOD, and significantly reverse pathological changes caused by iron homeostasis disorders (136). Collectively, these studies firmly confirm that iron chelators represented by DFO alleviate DR pathogenesis by regulating iron homeostasis and inhibiting oxidative stress and inflammation, and the FDA-approved clinical status of DFO further solidifies the translational feasibility of iron chelation therapy. However, these findings are mostly limited to single models, lacking data on distinct DR stages, ocular targeted delivery, long-term safety and efficacy, and comparisons with first-line clinical therapies. Coupled with the absence of clinical outcome measures and human clinical trial evidence, their direct clinical translation is restricted, highlighting an urgent need for more clinically relevant studies to optimize intervention strategies and clarify the actual therapeutic value of iron chelators in DR patients.

5.3 Research progress of natural products targeting ferroptosis for DR treatment

In recent years, natural compounds, with their structural diversity, chemical diversity, and rich biological activities, have become an important source for drug development. These breakthroughs have promoted the application research of natural products in the treatment of diabetic retinopathy (235). In recent years, it has been confirmed that natural products such as resveratrol, berberine, isoquercetin, platycodin D, and astragaloside IV can alleviate DR by inhibiting ferroptosis. AS-IV has been proven to effectively inhibit the death of RPE cells in DR induced by streptozotocin. Cellular changes show that AS-IV can inhibit cell damage caused by a high-sugar environment by increasing the expression of miR-128 (186). Studies have found that resveratrol can inhibit the apoptosis of retinal ganglion cells by inhibiting the Nrf2/HO-1 pathway and reducing retinal oxidative stress, thereby achieving the goal of treating DR (235). In addition, it has been found that most natural polyphenols play an antioxidant role by activating the Nrf2 and GPX4-related pathways, thereby playing an important role in the treatment of diabetes and its complications (228, 229, 236). Platycodin D (PLD) is a triterpenoid saponin isolated from the dried roots of Asarum heterotropoides. Studies have shown that PLD can exert therapeutic effects on DR in vivo by downregulating the ferroptosis-related TLR4/MyD88/NF-κB p65 pathway and upregulating the Nrf2/HO-1 pathway (226). In the high glucose cultured HRMECs model, intervention with berberine can upregulate the expression of Nrf2, HO-1, GPX4, and FSP1 while inhibiting ACSL4 (221). Isoquercetin can significantly alleviate retinal damage in mice with DR, and in vitro studies have confirmed that its protective effect is mediated by inhibiting the p53 signaling pathway (227). Pharmacological studies have also found that the total flavonoids (TFA) extracted from the flowers of Portulaca oleracea have functions similar to Fer-1. This component exerts its effects by activating the Nrf2 signaling pathway, reducing iron deposition, and enhancing antioxidant capacity (237). 1,8-Cineole reduces ferroptosis in retinal epithelial cells by inhibiting the PPAR-γ/TXNIP pathway (225). However, subsequent studies should focus on extract purification and structural modification to improve bioavailability, clarify precise molecular mechanisms with clinical samples, and conduct standardized preclinical studies with clinical outcomes as endpoints, so as to fully validate their therapeutic value and accelerate clinical translation for DR treatment.

6 Conclusions and perspectives

The pathophysiological mechanisms of DR are highly complex. Ferroptosis, a novel form of programmed cell death, involves intricate molecular mechanisms. This process is driven by iron-dependent peroxidation of phospholipids and is regulated by various cellular metabolic activities and signaling pathways. Although the pathophysiological role of ferroptosis is still being explored, its close association with DR has been confirmed. In relevant experiments, some ferroptosis inhibitors and iron chelators have shown good regulatory effects, and inhibiting ferroptosis can effectively prevent and delay the progression of the disease. Numerous natural products and drugs against ferroptosis also provide new ideas and targets for the treatment of DR. However, current research still has numerous critical shortcomings and bottlenecks to be addressed, which urgently require objective scrutiny and in-depth refinement. Most studies focus on the global regulation of blood-retinal barrier (BRB) function, and the cell-specific regulatory characteristics of ferroptosis in distinct retinal cell subtypes remain undefined, making it difficult to accurately distinguish the differential roles of cell-specific ferroptosis across various DR stages. The understanding of the specific regulatory mechanisms of organelles such as mitochondria and endoplasmic reticulum in ferroptosis, as well as the inter-organelle crosstalk network, is still limited. Additionally, the interactive crosstalk mechanisms between ferroptosis and other regulated cell death pathways have not been fully elucidated, failing to clarify the core position and synergistic mode of ferroptosis in the complex retinal cell death network of DR. In summary, more systematic and in-depth mechanistic and translational research is urgently needed to define the pivotal role of ferroptosis in DR pathogenesis and therapy. Comprehensive and in-depth dissection of the regulatory mechanisms, signaling networks and pathophysiological significance of ferroptosis can not only more clearly reveal its intrinsic association with DR, but also hold great promise for identifying novel diagnostic and therapeutic targets for DR, further deepen the understanding of the intricate pathophysiological processes of DR, and lay a fundamental theoretical foundation for developing precise and efficient ferroptosis-targeted therapeutic regimens for DR.

Author contributions

JJ: Methodology, Conceptualization, Writing – original draft, Investigation, Visualization, Writing – review & editing. ZL: Writing – review & editing, Project administration. XC: Funding acquisition, Writing – review & editing, Conceptualization, Project administration.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This study was funded by the National Natural Science Foundation of China (82374525), Scientific Research Project of the Education Department of Hunan Province (22A0250), Hunan Provincial Clinical Medical Research Center for Ophthalmic Diseases (Traditional Chinese Medicine) (2023SK4038), Key Scientific Research Project of Hunan Administration of Traditional Chinese Medicine (C2023013), Project on Advancing Clinical Evidence - based Capacity for Traditional Chinese Medicine - treated Diseases with Advantages (JBGS-A1-02) and Graduate Innovation Project of Hunan University of Chinese Medicine (2024CX025).

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. Cai K, Liu YP, and Wang D. Prevalence of diabetic retinopathy in patients with newly diagnosed type 2 diabetes:A systematic review and meta-analysisDiabetes/Metabolism Research and Reviews. Diabetes/Metabolism Res Rev. (2023) 39:e3586. doi: 10.1002/dmrr.3586

PubMed Abstract | Crossref Full Text | Google Scholar

2. Zhang C, Nie J, Feng L, Luo W, Yao J, Wang F, et al. The emerging roles of clusterin on reduction of both blood retina barrier breakdown and neural retina damage in diabetic retinopathy. Discov Med. (2016) 21:227–37.

PubMed Abstract | Google Scholar

3. 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

4. Sun Y, Zheng Y, Wang C, and Liu Y. Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells. Cell Death Dis. (2018) 9:753. doi: 10.1038/s41419-018-0794-4

PubMed Abstract | Crossref Full Text | Google Scholar

5. Ouyang J, Zhou L, and Wang Q. Spotlight on iron and ferroptosis: research progress in diabetic retinopathy. Front Endocrinol. (2023) 14:1234824. doi: 10.3389/fendo.2023.1234824

PubMed Abstract | Crossref Full Text | Google Scholar

6. Wu D and Chen L. Ferroptosis: a novel cell death form will be a promising therapy target for diseases. Acta Biochim Biophys Sin (Shanghai). (2015) 47:857–9. doi: 10.1093/abbs/gmv086

PubMed Abstract | Crossref Full Text | Google Scholar

7. Liu P, Zhang Z, Cai Y, Li Z, Zhou Q, and Chen Q. Ferroptosis: Mechanisms and role in diabetes mellitus and its complications. Ageing Res Rev. (2024) 94:102201. doi: 10.1016/j.arr.2024.102201

PubMed Abstract | Crossref Full Text | Google Scholar

8. Li L, Dai Y, Ke D, Liu J, Chen P, Wei D, et al. Ferroptosis: new insight into the mechanisms of diabetic nephropathy and retinopathy. Front Endocrinol. (2023) 14:1215292. doi: 10.3389/fendo.2023.1215292

PubMed Abstract | Crossref Full Text | Google Scholar

9. Zhou J, Sun C, Dong X, and Wang H. A novel miR-338-3p/SLC1A5 axis reprograms retinal pigment epithelium to increases its resistance to high glucose-induced cell ferroptosis. J Mol Histol. (2022) 53:561–71. doi: 10.1007/s10735-022-10070-0

PubMed Abstract | Crossref Full Text | Google Scholar

10. Lei X, Wang X, and Zhang X. YY2 mediates transcriptional repression of PHGDH and expedites oxidative stress in retinal pigment epithelial cells in diabetic retinopathy. J Diabetes Invest. (2025) 16:775–90. doi: 10.1111/jdi.70011

PubMed Abstract | Crossref Full Text | Google Scholar

11. Yuan F, Han S, Li Y, Li S, Li D, Tian Q, et al. miR-214-3p attenuates ferroptosis-induced cellular damage in a mouse model of diabetic retinopathy through the p53/SLC7A11/GPX4 axis. Exp Eye Res. (2025) 253:110299. doi: 10.1016/j.exer.2025.110299

PubMed Abstract | Crossref Full Text | Google Scholar

12. Henning Y, Blind US, Larafa S, Matschke J, and Fandrey J. Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction. Cell Death Dis. (2022) 13:662. doi: 10.1038/s41419-022-05121-z

PubMed Abstract | Crossref Full Text | Google Scholar

13. Massaiu I, Campodonico J, Mapelli M, Salvioni E, Valerio V, Moschetta D, et al. Dysregulation of iron metabolism-linked genes at myocardial tissue and cell levels in dilated cardiomyopathy. IJMS. (2023) 24:2887. doi: 10.3390/ijms24032887

PubMed Abstract | Crossref Full Text | Google Scholar

14. Sarkar S, Kannan R, Panigrahi T, Veeramani K, Mb T, Shanker Bhattacharya S, et al. Comparative transcriptomic analysis of retinal response to diverse cellular stresses reveals relative contributions of different cell death processes and signalling networks. Cell Death Dis. (2025) 16:876. doi: 10.1038/s41419-025-08257-w

PubMed Abstract | Crossref Full Text | Google Scholar

15. Li J, Cao F, Yin H, Huang Z, Lin Z, 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. Zhang J, Du J, Kong N, Zhang G, Liu M, and Liu C. Mechanisms and pharmacological applications of ferroptosis: a narrative review. Ann Transl Med. (2021) 9:1503–3. doi: 10.21037/atm-21-1595

PubMed Abstract | Crossref Full Text | Google Scholar

17. Namgaladze D, Fuhrmann DC, and Brüne B. Interplay of Nrf2 and BACH1 in inducing ferroportin expression and enhancing resistance of human macrophages towards ferroptosis. Cell Death Discov. (2022) 8:327. doi: 10.1038/s41420-022-01117-y

PubMed Abstract | Crossref Full Text | Google Scholar

18. Jiang Q, Wan R, Jiang J, Li T, Li Y, Yu S, et al. Interaction between macrophages and ferroptosis: Metabolism, function, and diseases. Chin Med J (Engl). (2025) 138:509–22. doi: 10.1097/CM9.0000000000003189

PubMed Abstract | Crossref Full Text | Google Scholar

19. Tang D, Chen X, Kang R, and Kroemer G. Ferroptosis: molecular mechanisms and health implications. Cell Res. (2021) 31:107–25. doi: 10.1038/s41422-020-00441-1

PubMed Abstract | Crossref Full Text | Google Scholar

20. Yu Y, Jiang L, Wang H, Shen Z, Cheng Q, Zhang P, et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood. (2020) 136:726–39. doi: 10.1182/blood.2019002907

PubMed Abstract | Crossref Full Text | Google Scholar

21. Bao W, Pang P, Zhou X, 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

22. Kim J, Kim J, and Kim MS. The intersection of glycosylation and ferroptosis in cancer. Antioxidants. (2025) 14:1077. doi: 10.3390/antiox14091077

PubMed Abstract | Crossref Full Text | Google Scholar

23. Bao W, Zhou X, Zhou L, Wang F, Yin X, Lu Y, et al. Targeting miR-124/Ferroportin signaling ameliorated neuronal cell death through inhibiting apoptosis and ferroptosis in aged intracerebral hemorrhage murine model. Aging Cell. (2020) 19:e13235. doi: 10.1111/acel.13235

PubMed Abstract | Crossref Full Text | Google Scholar

24. Xie J, Lv H, Liu X, Xia Z, Li J, Hong E, et al. Nox4-and Tf/TfR-mediated peroxidation and iron overload exacerbate neuronal ferroptosis after intracerebral hemorrhage: Involvement of EAAT3 dysfunction. Free Radical Biol Med. (2023) 199:67–80. doi: 10.1016/j.freeradbiomed.2023.02.015

PubMed Abstract | Crossref Full Text | Google Scholar

25. Xia H, Wu Y, Zhao J, Cheng C, Lin J, Yang Y, et al. N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2. Cell Death Differ. (2023) 30:1293–304. doi: 10.1038/s41418-023-01138-9

PubMed Abstract | Crossref Full Text | Google Scholar

26. Xiong L, Gao X, Wang L, Luo L, Su J, Wang Y, et al. The influence of ferroptosis-associated gene HSPA5 on the prognosis and immune evasion of lung adenocarcinoma. Discov Onc. (2025) 16:1868. doi: 10.1007/s12672-025-03629-2

PubMed Abstract | Crossref Full Text | Google Scholar

27. Kameda K, Yanagiya R, Miyatake Y, Carreras J, Higuchi H, Murayama H, et al. Hepatic niche leads to aggressive natural killer cell leukemia proliferation through transferrin-transferrin receptor 1 axis. Blood J. (2023) 142:352–64. doi: 10.1182/blood.2022018597

PubMed Abstract | Crossref Full Text | Google Scholar

28. Kwon M, Park E, Lee S, and Chung S. Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death. Oncotarget. (2015) 6:24393–403. doi: 10.18632/oncotarget.5162

PubMed Abstract | Crossref Full Text | Google Scholar

29. Zhu R, Zhang Y, Wang Y, Bao X, Zhang L, Fang J, et al. Titanium nanoparticles provoke ferritinophagy-mediated ferroptosis via inhibition of the Nrf2-HO-1 signaling pathway in osteocytes. Toxicology. (2026) 519:154324. doi: 10.1016/j.tox.2025.154324

PubMed Abstract | Crossref Full Text | Google Scholar

30. Shin J, Hwang Y, Park H, Choi H, Chang Y, Na K, et al. Renoprotective effects of MIT -001 in ischemia–reperfusion injury: modulation of ferroptosis, ROS and fibrotic markers. J Cell Mol Medi. (2025) 29:e70914. doi: 10.1111/jcmm.70914

PubMed Abstract | Crossref Full Text | Google Scholar

31. Mitchell SB and Aydemir TB. Roles of zinc and zinc transporters in development, progression, and treatment of inflammatory bowel disease (IBD). Front Nutr. (2025) 12:1649658. doi: 10.3389/fnut.2025.1649658

PubMed Abstract | Crossref Full Text | Google Scholar

32. Li Y, Shi C, Liu R, Yang J, and Wang J. Alpha-synuclein affects certain iron transporters of BV2 microglia cell through its ferric reductase activity. J Neurophysiology. (2024) 132:446–53. doi: 10.1152/jn.00106.2024

PubMed Abstract | Crossref Full Text | Google Scholar

33. Ghosh M, Zhang D, Ollivierre W, Noguchi A, Springer D, Linehan W, et al. Therapeutic inhibition of HIF-2α reverses polycythemia and pulmonary hypertension in murine models of human diseases. Blood. (2021) 137:2509–19. doi: 10.1182/blood.2020009138

PubMed Abstract | Crossref Full Text | Google Scholar

34. Zhang D, Ollivierre H, Qi C, and Rouault T. A bulge uridine in the HIF2α IRE allows IRP1 but not IRP2 to selectively regulate HIF2α expression and ensuing EPO levels. Blood. (2025) 145:533–42. doi: 10.1182/blood.2024025246

PubMed Abstract | Crossref Full Text | Google Scholar

35. Yang Y, Lin Y, Han Z, Wang B, and Zheng W. Ferroptosis: a novel mechanism of cell death in ophthalmic conditions. Front Immunol. (2024) 15:1440309. doi: 10.3389/fimmu.2024.1440309

PubMed Abstract | Crossref Full Text | Google Scholar

36. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. (2017) 13:81–90. doi: 10.1038/nchembio.2238

PubMed Abstract | Crossref Full Text | Google Scholar

37. 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

38. Hou X, Li H, Jie C, Liu Z, Bi X, Wang J, et al. Identification of important biomarkers associated with ferroptosis in diabetic retinopathy via integrative bioinformatics analysis. Exp Eye Res. (2025) 259:110527. doi: 10.1016/j.exer.2025.110527

PubMed Abstract | Crossref Full Text | Google Scholar

39. Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol. (2015) 10:1604–9. doi: 10.1021/acschembio.5b00245

PubMed Abstract | Crossref Full Text | Google Scholar

40. Zhang H, Hu B, Li Z, Du T, Shan J, Ye Z, 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

41. Liu X, Chen Y, Zhang L, Qi Z, Yang L, Huang C, et al. Taurine attenuates disuse muscle atrophy through modulation of the xCT-GSH-GPX4 and AMPK-ACC-ACSL4 pathways. Antioxidants. (2025) 14:847. doi: 10.3390/antiox14070847

PubMed Abstract | Crossref Full Text | Google Scholar

42. Noguchi N, Saito Y, and Niki E. Lipid peroxidation, ferroptosis, and antioxidants. Free Radic Biol Med. (2025) 237:228–38. doi: 10.1016/j.freeradbiomed.2025.05.393

PubMed Abstract | Crossref Full Text | Google Scholar

43. Chu B, Kon N, Chen D, Li T, Liu T, Jiang L, et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat Cell Biol. (2019) 21:579–91. doi: 10.1038/s41556-019-0305-6

PubMed Abstract | Crossref Full Text | Google Scholar

44. Zhou R, Chen Y, Wei X, Yu B, Xiong Z, Lu C, et al. Novel insights into ferroptosis: Implications for age-related diseases. Theranostics. (2020) 10:11976–97. doi: 10.7150/thno.50663

PubMed Abstract | Crossref Full Text | Google Scholar

45. Lapaquette P, Terrat S, Proukhnitzky L, Martine L, Grégoire S, Buteau B, et al. Long-term intake of Lactobacillus helveticus enhances bioavailability of omega-3 fatty acids in the mouse retina. NPJ Biofilms Microbiomes. (2024) 10:4. doi: 10.1038/s41522-023-00474-5

PubMed Abstract | Crossref Full Text | Google Scholar

46. Girotti AW and Korytowski W. Cholesterol hydroperoxide generation, translocation, and reductive turnover in biological systems. Cell Biochem Biophys. (2017) 75:413–9. doi: 10.1007/s12013-017-0799-0

PubMed Abstract | Crossref Full Text | Google Scholar

47. Girotti AW and Korytowski W. Trafficking of oxidative stress-generated lipid hydroperoxides: pathophysiological implications. Free Radical Res. (2023) 57:130–9. doi: 10.1080/10715762.2023.2213817

PubMed Abstract | Crossref Full Text | Google Scholar

48. Polo-Barranco A, Rebolledo-Maldonado C, Esquiaqui-Rangel V, Nuñez-Mejia A, Rambal-Torres J, Barraza-Ahumada V, et al. Diabetes mellitus and lipoprotein(a): A determinant interaction in micro- and macrovascular damage. IJMS. (2025) 26:11427. doi: 10.3390/ijms262311427

PubMed Abstract | Crossref Full Text | Google Scholar

49. Fliesler SJ and Bretillon L. The ins and outs of cholesterol in the vertebrate retina. J Lipid Res. (2010) 51:3399–413. doi: 10.1194/jlr.R010538

PubMed Abstract | Crossref Full Text | Google Scholar

50. Fliesler SJ and Keller RK. Metabolism of [3H] farnesol to cholesterol and cholesterogenic intermediates in the living rat eye. Biochem Biophys Res Commun. (1995) 210:695–702. doi: 10.1006/bbrc.1995.1715

PubMed Abstract | Crossref Full Text | Google Scholar

51. Lin J, Mast N, Bederman I, Li Y, Brunengraber H, Björkhem I, et al. Cholesterol in mouse retina originates primarily from in situ de novo biosynthesis. J Lipid Res. (2016) 57:258–64. doi: 10.1194/jlr.M064469

PubMed Abstract | Crossref Full Text | Google Scholar

52. Zheng W, Reem RE, Omarova S, Huang S, DiPatre PL, Charvet CD, et al. Spatial distribution of the pathways of cholesterol homeostasis in human retina. PloS One. (2012) 7:e37926. doi: 10.1371/journal.pone.0037926

PubMed Abstract | Crossref Full Text | Google Scholar

53. Busik JV. Lipid metabolism dysregulation in diabetic retinopathy. J Lipid Res. (2021) 62:100017. doi: 10.1194/jlr.TR120000981

PubMed Abstract | Crossref Full Text | Google Scholar

54. Yu JY, Du M, Elliott MH, Wu M, Fu D, Yang S, et al. Extravascular modified lipoproteins: a role in the propagation of diabetic retinopathy in a mouse model of type 1 diabetes. Diabetologia. (2016) 59:2026–35. doi: 10.1007/s00125-016-4012-6

PubMed Abstract | Crossref Full Text | Google Scholar

55. Zhu Y, Zhao W, Li W, Wang J, Chen H, Wang Z, et al. Squalene epoxidase promotes paraquat-induced pulmonary toxicity through endoplasmic reticulum-mediated ferroptosis. J Advanced Res. (2025) 1:S2090-1232(25)00385-6. doi: 10.1016/j.jare.2025.05.064

PubMed Abstract | Crossref Full Text | Google Scholar

56. Picón DF and Skouta R. Unveiling the therapeutic potential of squalene synthase: deciphering its biochemical mechanism, disease implications, and intriguing ties to ferroptosis. Cancers. (2023) 15:3731. doi: 10.3390/cancers15143731

PubMed Abstract | Crossref Full Text | Google Scholar

57. Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. (2014) 16:1180–91. doi: 10.1038/ncb3064

PubMed Abstract | Crossref Full Text | Google Scholar

58. Sun Q, Liu D, Cui W, Cheng H, Huang L, Zhang R, et al. Cholesterol mediated ferroptosis suppression reveals essential roles of Coenzyme Q and squalene. Commun Biol. (2023) 6:1108. doi: 10.1038/s42003-023-05477-8

PubMed Abstract | Crossref Full Text | Google Scholar

59. Tikhonenko M, Lydic TA, Opreanu M, Li Calzi S, Bozack S, McSorley KM, et al. N-3 polyunsaturated Fatty acids prevent diabetic retinopathy by inhibition of retinal vascular damage and enhanced endothelial progenitor cell reparative function. PloS One. (2013) 8:e55177. doi: 10.1371/journal.pone.0055177

PubMed Abstract | Crossref Full Text | Google Scholar

60. Opreanu M, Tikhonenko M, Bozack S, Lydic TA, Reid GE, McSorley KM, et al. The unconventional role of acid sphingomyelinase in regulation of retinal microangiopathy in diabetic human and animal models. Diabetes. (2011) 60:2370–8. doi: 10.2337/db10-0550

PubMed Abstract | Crossref Full Text | Google Scholar

61. Chakravarthy H, Navitskaya S, O'Reilly S, Gallimore J, Mize H, Beli E, et al. Role of acid sphingomyelinase in shifting the balance between proinflammatory and reparative bone marrow cells in diabetic retinopathy. Stem Cells. (2016) 34:972–83. doi: 10.1002/stem.2259

PubMed Abstract | Crossref Full Text | Google Scholar

62. Jiang WG, Bryce RP, Horrobin DF, and Mansel RE. Regulation of tight junction permeability and occludin expression by polyunsaturated fatty acids. Biochem Biophys Res Commun. (1998) 244:414–20. doi: 10.1006/bbrc.1998.8288

PubMed Abstract | Crossref Full Text | Google Scholar

63. Fotiadis D, Kanai Y, and Palacín M. The SLC3 and SLC7 families of amino acid transporters. Mol Aspects Med. (2013) 34:139–58. doi: 10.1016/j.mam.2012.10.007

PubMed Abstract | Crossref Full Text | Google Scholar

64. Ghosh A, Gao L, Thakur A, Siu PM, and Lai CWK. Role of free fatty acids in endothelial dysfunction. J BioMed Sci. (2017) 24:50. doi: 10.1186/s12929-017-0357-5

PubMed Abstract | Crossref Full Text | Google Scholar

65. Yan P, Tang S, Zhang H, Guo Y, Zeng Z, Wen Q, et al. Nerve growth factor protects against palmitic acid-induced injury in retinal ganglion cells. Neural Regener Res. (2016) 11:1851. doi: 10.4103/1673-5374.194758

PubMed Abstract | Crossref Full Text | Google Scholar

66. Mao Z, Yang W, Chao Y, Chen Z, and Zou Y. Palmitic acid induces ferroptosis in retinal microvascular endothelial cells by palmitoylation of keap1 to affect diabetic retinopathy. Invest Ophthalmol Vis Sci. (2025) 66:41. doi: 10.1167/iovs.66.14.41

PubMed Abstract | Crossref Full Text | Google Scholar

67. Johns I, Frost G, and Dornhorst A. Increasing the proportion of plasma MUFA, as a result of dietary intervention, is associated with a modest improvement in insulin sensitivity. J Nutr Sci. (2020) 9:e6. doi: 10.1017/jns.2019.29

PubMed Abstract | Crossref Full Text | Google Scholar

68. Wang Z, Wang H, Chen Y, Chen Y, Zhang X, Diwon A, et al. Deciphering the role of oleic acid in diabetic retinopathy: an empirical analysis of monounsaturated fatty acids. Nutr Metab (Lond). (2024) 21:97. doi: 10.1186/s12986-024-00874-0

PubMed Abstract | Crossref Full Text | Google Scholar

69. Kulacoglu D. Alterations of fatty acid composition of erythrocyte membrane in type 2 diabetes patients with diabetic retinopathy. Japanese J Ophthalmology. (2003) 47:551–6. doi: 10.1016/j.jjo.2003.08.009

PubMed Abstract | Crossref Full Text | Google Scholar

70. Yang W, 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

71. Sato H, Nomura S, Maebara K, Sato K, Tamba M, and Bannai S. Transcriptional control of cystine/glutamate transporter gene by amino acid deprivation. Biochem Biophys Res Commun. (2004) 325:109–16. doi: 10.1016/j.bbrc.2004.10.009

PubMed Abstract | Crossref Full Text | Google Scholar

72. Qiu H, Liu J, Shao N, Zhao J, Chen C, Jiang Y, et al. SLC7A11 as a bridge between ferroptosis and disulfidptosis: a promising target for tumor treatment. Cell Commun Signal. (2025) 23:460. doi: 10.1186/s12964-025-02447-x

PubMed Abstract | Crossref Full Text | Google Scholar

73. Zhang Y, Swanda RV, Nie L, Liu X, Wang C, Lee H, et al. mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat Commun. (2021) 12:1589. doi: 10.1038/s41467-021-21841-w

PubMed Abstract | Crossref Full Text | Google Scholar

74. Yang Y, Liu M, Dong X, Bai J, Shi W, Zhu Q, et al. Naringin suppresses coCl2-induced ferroptosis in ARPE-19 cells. Antioxidants. (2025) 14:236. doi: 10.3390/antiox14020236

PubMed Abstract | Crossref Full Text | Google Scholar

75. Zhang M, Chen X, and Zhang Y. Mechanisms of vitamins inhibiting ferroptosis. Antioxidants. (2024) 13:1571. doi: 10.3390/antiox13121571

PubMed Abstract | Crossref Full Text | Google Scholar

76. Fujihara KM, Zhang BZ, and Clemons NJ. Opportunities for ferroptosis in cancer therapy. Antioxidants. (2021) 10:986. doi: 10.3390/antiox10060986

PubMed Abstract | Crossref Full Text | Google Scholar

77. Ma S, Qin J, Zhang Y, Luan J, Sun N, Hou G, et al. Disrupting mitochondrial dynamics attenuates ferroptosis and chemotoxicity via upregulating NRF2-mediated FSP1 expression. Cell Rep. (2025) 44:116234. doi: 10.1016/j.celrep.2025.116234

PubMed Abstract | Crossref Full Text | Google Scholar

78. Svobodová L, Sedlácek J, Šmahelová Z, Majer P, Machara A, and Šašková KG. Targeting NFE2L1 signalling with small molecules to protect against Ferroptosis. Bioorganic Medicinal Chem Letters. (2026) 130:130425. doi: 10.1016/j.bmcl.2025.130425

PubMed Abstract | Crossref Full Text | Google Scholar

79. Shao J, Bai Z, Zhang L, and Zhang F. Ferrostatin-1 alleviates tissue and cell damage in diabetic retinopathy by improving the antioxidant capacity of the Xc–GPX4 system. Cell Death Discov. (2022) 8:426. doi: 10.1038/s41420-022-01141-y

PubMed Abstract | Crossref Full Text | Google Scholar

80. Fan X, Xu M, Ren Q, Fan Y, Liu B, Chen J, et al. Downregulation of fatty acid binding protein 4 alleviates lipid peroxidation and oxidative stress in diabetic retinopathy by regulating peroxisome proliferator-activated receptor γ-mediated ferroptosis. Bioengineered. (2022) 13:10540–51. doi: 10.1080/21655979.2022.2062533

PubMed Abstract | Crossref Full Text | Google Scholar

81. Giri B, Dey S, Das T, Sarkar M, Banerjee J, and Dash SK. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomedicine Pharmacotherapy. (2018) 107:306–28. doi: 10.1016/j.biopha.2018.07.157

PubMed Abstract | Crossref Full Text | Google Scholar

82. Nagakannan P, Islam MI, Sultana S, Karimi-Abdolrezaee S, and Eftekharpour E. TXNIP promotes ferroptosis through NCOA4 mediated ferritinophagy. Biochim Biophys Acta (BBA) - Mol Cell Res. (2025) 1872:120054. doi: 10.1016/j.bbamcr.2025.120054

PubMed Abstract | Crossref Full Text | Google Scholar

83. Luo L, Cai Y, Jiang Y, Gong Y, Cai C, Lai D, et al. Pipecolic acid mitigates ferroptosis in diabetic retinopathy by regulating GPX4-YAP signaling. Biomedicine Pharmacotherapy. (2023) 169:115895. doi: 10.1016/j.biopha.2023.115895

PubMed Abstract | Crossref Full Text | Google Scholar

84. Dächert J, Schoeneberger H, Rohde K, and Fulda S. RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death. Oncotarget. (2016) 7:63779–92. doi: 10.18632/oncotarget.11687

PubMed Abstract | Crossref Full Text | Google Scholar

85. Arnér ESJ and Schmidt EE. Unresolved questions regarding cellular cysteine sources and their possible relationships to ferroptosis. Adv Cancer Res. (2024) 162:1–44. doi: 10.1016/bs.acr.2024.04.001

PubMed Abstract | Crossref Full Text | Google Scholar

86. Lee J and Roh JL. Cysteine metabolism at the crossroads of ferroptosis and cancer therapy. Crit Rev Oncology/Hematology. (2025) 215:104906. doi: 10.1016/j.critrevonc.2025.104906

PubMed Abstract | Crossref Full Text | Google Scholar

87. Liu X, Zhao Z, Bian Z, Benthani FA, Hu Y, Liang D, et al. Endocytosis is essential for cysteine-deprivation-induced ferroptosis. Mol Cell. (2025) 85:3333–3342.e4. doi: 10.1016/j.molcel.2025.08.006

PubMed Abstract | Crossref Full Text | Google Scholar

88. Russier M, Fiore A, Bici A, Groß A, Tanzer M, Yeroslaviz A, et al. Differential cell survival outcomes in response to diverse amino acid stress. Life Sci Alliance. (2025) 8:e202503324. doi: 10.26508/lsa.202503324

PubMed Abstract | Crossref Full Text | Google Scholar

89. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife. (2014) 3:e02523. doi: 10.7554/eLife.02523

PubMed Abstract | Crossref Full Text | Google Scholar

90. Gao M, Monian P, Quadri N, Ramasamy R, and Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. (2015) 59:298–308. doi: 10.1016/j.molcel.2015.06.011

PubMed Abstract | Crossref Full Text | Google Scholar

91. Amiri-Dashatan N, Etemadi SM, Besharati S, Farahani M, and Moghaddam AK. Dysregulation of amino acids balance as potential serum-metabolite biomarkers for diagnosis and prognosis of diabetic retinopathy: a metabolomics study. J Diabetes Metab Disord. (2024) 23:2031–42. doi: 10.1007/s40200-024-01462-y

PubMed Abstract | Crossref Full Text | Google Scholar

92. Holeček M. Role of impaired glycolysis in perturbations of amino acid metabolism in diabetes mellitus. IJMS. (2023) 24:1724. doi: 10.3390/ijms24021724

PubMed Abstract | Crossref Full Text | Google Scholar

93. Bloomgarden Z. Diabetes and branched-chain amino acids: W hat is the link? J Diabetes. (2018) 10:350–2. doi: 10.1111/1753-0407.12645

PubMed Abstract | Crossref Full Text | Google Scholar

94. Li Q, Yu X, Yu R, Shi X, and Lu Y. Therapeutic potential of inhibiting hmox1 in sepsis-induced lung injury: A molecular mechanism study. J Biochem Mol Tox. (2025) 39:e70134. doi: 10.1002/jbt.70134

PubMed Abstract | Crossref Full Text | Google Scholar

95. Lee D and Smith LEH. Therapeutic effects of taurine and histidine supplementation in retinal diseases. Life. (2024) 14:1566. doi: 10.3390/life14121566

PubMed Abstract | Crossref Full Text | Google Scholar

96. Han F, Xu C, Hangfu X, Liu Y, Zhang Y, Sun B, et al. Circulating glutamine/glutamate ratio is closely associated with type 2 diabetes and its associated complications. Front Endocrinol. (2024) 15:1422674. doi: 10.3389/fendo.2024.1422674

PubMed Abstract | Crossref Full Text | Google Scholar

97. Gregory A, Yumnamcha T, Shawky M, Eltanani S, Naghdi A, Ross BX, et al. The Warburg effect alters amino acid homeostasis in human retinal endothelial cells: implication for proliferative diabetic retinopathy. Sci Rep. (2023) 13:15973. doi: 10.1038/s41598-023-43022-z

PubMed Abstract | Crossref Full Text | Google Scholar

98. Warden C, Zubieta D, and Brantley MA. Citrulline plus arginine induces an angiogenic response and increases permeability in retinal endothelial cells via nitric oxide production. IJMS. (2025) 26:2080. doi: 10.3390/ijms26052080

PubMed Abstract | Crossref Full Text | Google Scholar

99. Corano Scheri K, Hsieh YW, Tedeschi T, Hurley JB, and Fawzi AA. Müller cell glutamine metabolism links photoreceptor and endothelial injury in diabetic retinopathy. Life Sci Alliance. (2026) 9:e202503434. doi: 10.26508/lsa.202503434

PubMed Abstract | Crossref Full Text | Google Scholar

100. Yuan J, Lv T, Yang J, Wu Z, Yan L, Yang J, et al. HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma. Redox Biol. (2022) 58:102546. doi: 10.1016/j.redox.2022.102546

PubMed Abstract | Crossref Full Text | Google Scholar

101. Lv Y, Liang C, Sun Q, Zhu J, Xu H, Li X, et al. Structural insights into FSP1 catalysis and ferroptosis inhibition. Nat Commun. (2023) 14:5933. doi: 10.1038/s41467-023-41626-7

PubMed Abstract | Crossref Full Text | Google Scholar

102. Baschiera E, Sorrentino U, Calderan C, Desbats MA, and Salviati L. The multiple roles of coenzyme Q in cellular homeostasis and their relevance for the pathogenesis of coenzyme Q deficiency. Free Radical Biol Med. (2021) 166:277–86. doi: 10.1016/j.freeradbiomed.2021.02.039

PubMed Abstract | Crossref Full Text | Google Scholar

103. 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

104. 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

105. Yang M, Tsui MG, Tsang JKW, Goit RK, Yao KM, So KF, et al. Involvement of FSP1-CoQ10-NADH and GSH-GPx-4 pathways in retinal pigment epithelium ferroptosis. Cell Death Dis. (2022) 13:468. doi: 10.1038/s41419-022-04924-4

PubMed Abstract | Crossref Full Text | Google Scholar

106. Zhang T, Ouyang H, Mei X, Lu B, Yu Z, Chen K, et al. Erianin alleviates diabetic retinopathy by reducing retinal inflammation initiated by microglial cells via inhibiting hyperglycemia-mediated ERK1/2–NF-κB signaling pathway. FASEB J. (2019) 33:11776–90. doi: 10.1096/fj.201802614RRR

PubMed Abstract | Crossref Full Text | Google Scholar

107. Madak JT, Bankhead A 3rd, Cuthbertson CR, Showalter HD, and Neamati N. Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer. Pharmacol Ther. (2019) 195:111–31. doi: 10.1016/j.pharmthera.2018.10.012

PubMed Abstract | Crossref Full Text | Google Scholar

108. ao C, Liu X, Zhang Y, Lei G, Yan Y, Lee H, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature. (2021) 593:586–90. doi: 10.1038/s41586-021-03539-7

PubMed Abstract | Crossref Full Text | Google Scholar

109. Cao J, Chen X, Chen L, Lu Y, Wu Y, Deng A, et al. DHODH-mediated mitochondrial redox homeostasis: a novel ferroptosis regulator and promising therapeutic target. Redox Biol. (2025) 85:103788. doi: 10.1016/j.redox.2025.103788

PubMed Abstract | Crossref Full Text | Google Scholar

110. Vyas V K and Ghate M. Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors. MRMC. (2011) 11:1039–55. doi: 10.2174/138955711797247707

PubMed Abstract | Crossref Full Text | Google Scholar

111. Kraft VAN, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent Sci. (2020) 6:41–53. doi: 10.1021/acscentsci.9b01063

PubMed Abstract | Crossref Full Text | Google Scholar

112. McNeill E, Crabtree MJ, Sahgal N, Patel J, Chuaiphichai S, Iqbal AJ, et al. Regulation of iNOS function and cellular redox state by macrophage Gch1 reveals specific requirements for tetrahydrobiopterin in NRF2 activation. Free Radical Biol Med. (2015) 79:206–16. doi: 10.1016/j.freeradbiomed.2014.10.575

PubMed Abstract | Crossref Full Text | Google Scholar

113. Wang D, Liang W, Huo D, Wang H, Wang Y, Cong C, et al. SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1. Cell Death Differ. (2023) 30:369–82. doi: 10.1038/s41418-022-01089-7

PubMed Abstract | Crossref Full Text | Google Scholar

114. Lohmann K, Redin C, Tönnies H, Bressman SB, Subero JIM, Wiegers K, et al. Complex and dynamic chromosomal rearrangements in a family with seemingly non-mendelian inheritance of dopa-responsive dystonia. JAMA Neurol. (2017) 74:806. doi: 10.1001/jamaneurol.2017.0666

PubMed Abstract | Crossref Full Text | Google Scholar

115. Zhong R, Yang H, Li X, Wang F, Zhai L, and Gao J. Mitochondria-mediated mechanisms of ferroptosis in neurological diseases. Neurochem Res. (2025) 50:354. doi: 10.1007/s11064-025-04605-6

PubMed Abstract | Crossref Full Text | Google Scholar

116. Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: process and function. Cell Death Differ. (2016) 23:369–79. doi: 10.1038/cdd.2015.158

PubMed Abstract | Crossref Full Text | Google Scholar

117. Lipper CH, Stofleth JT, Bai F, Sohn YS, Roy S, Mittler R, et al. Redox-dependent gating of VDAC by mitoNEET. Proc Natl Acad Sci USA. (2019) 116:19924–9. doi: 10.1073/pnas.1908271116

PubMed Abstract | Crossref Full Text | Google Scholar

118. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, et al. RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. (2007) 447:865–9. doi: 10.1038/nature05859

PubMed Abstract | Crossref Full Text | Google Scholar

119. Simamura E, Shimada H, Hatta T, and Hirai KI. Mitochondrial voltage-dependent anion channels (VDACs) as novel pharmacological targets for anti-cancer agents. J Bioenerg Biomembr. (2008) 40:213–7. doi: 10.1007/s10863-008-9158-6

PubMed Abstract | Crossref Full Text | Google Scholar

120. Lill R and Freibert SA. Mechanisms of mitochondrial iron-sulfur protein biogenesis. Annu Rev Biochem. (2020) 89:471–99. doi: 10.1146/annurev-biochem-013118-111540

PubMed Abstract | Crossref Full Text | Google Scholar

121. Jelinek A, Heyder L, Daude M, Plessner M, Krippner S, Grosse R, et al. Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis. Free Radical Biol Med. (2018) 117:45–57. doi: 10.1016/j.freeradbiomed.2018.01.019

PubMed Abstract | Crossref Full Text | Google Scholar

122. Merkel M, Goebel B, Boll M, Adhikari A, Maurer V, Steinhilber D, et al. Mitochondrial reactive oxygen species formation determines ACSL4/LPCAT2-mediated ferroptosis. Antioxidants. (2023) 12:1590. doi: 10.3390/antiox12081590

PubMed Abstract | Crossref Full Text | Google Scholar

123. Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O, Penna A, et al. Genome-wide RNAi screen of Ca²⁺ influx identifies genes that regulate Ca²⁺ release-activated Ca²⁺ channel activity. Proc Natl Acad Sci USA. (2006) 103:9357–62. doi: 10.1073/pnas.0603161103

PubMed Abstract | Crossref Full Text | Google Scholar

124. Maher P, van Leyen K, Dey PN, Honrath B, Dolga A, and Methner A. The role of Ca2+ in cell death caused by oxidative glutamate toxicity and ferroptosis. Cell Calcium. (2018) 70:47–55. doi: 10.1016/j.ceca.2017.05.007

PubMed Abstract | Crossref Full Text | Google Scholar

125. Xu Y, Li Y, Li J, and Chen W. Ethyl carbamate triggers ferroptosis in liver through inhibiting GSH synthesis and suppressing Nrf2 activation. Redox Biol. (2022) 53:102349. doi: 10.1016/j.redox.2022.102349

PubMed Abstract | Crossref Full Text | Google Scholar

126. Anandhan A, Dodson M, Shakya A, Chen J, Liu P, Wei Y, et al. NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8. Sci Adv. (2023) 9:eade9585. doi: 10.1126/sciadv.ade9585

PubMed Abstract | Crossref Full Text | Google Scholar

127. Moi P, Chan K, Asunis I, Cao A, and Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA. (1994) 91:9926–30. doi: 10.1073/pnas.91.21.9926

PubMed Abstract | Crossref Full Text | Google Scholar

128. Shen Y, Shen X, Wang S, Zhang Y, Wang Y, Ding Y, et al. Protective effects of Salvianolic acid B on rat ferroptosis in myocardial infarction through upregulating the Nrf2 signaling pathway. Int Immunopharmacology. (2022) 112:109257. doi: 10.1016/j.intimp.2022.109257

PubMed Abstract | Crossref Full Text | Google Scholar

129. Cheng H, Wang P, Wang N, Dong W, Chen Z, Wu M, et al. Neuroprotection of NRF2 against Ferroptosis after Traumatic Brain Injury in Mice. Antioxidants. (2023) 12:731. doi: 10.3390/antiox12030731

PubMed Abstract | Crossref Full Text | Google Scholar

130. Luo X, Wang Y, Zhu X, Chen Y, Xu B, Bai X, et al. MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction. Redox Biol. (2024) 69:102987. doi: 10.1016/j.redox.2023.102987

PubMed Abstract | Crossref Full Text | Google Scholar

131. Li Y, Ma X, Xing Y, Dong C, Feng L, Huo R, et al. Exploring nrf2 as a potential biomarker in asthma: links to hypoxia, oxidative stress, and ferroptosis in a cross-sectional study. J Asthma Allergy. (2025) 18:1439–53. doi: 10.2147/JAA.S520012

PubMed Abstract | Crossref Full Text | Google Scholar

132. Colyn L, Grube J, Wang C, Dietrich J, Kühnel M, Reinders J, et al. Keap1 deletion rescues cell death associated with gpx4 loss in hepatocytes during acute liver injury. Liver Int. (2025) 45:e70210. doi: 10.1111/liv.70210

PubMed Abstract | Crossref Full Text | Google Scholar

133. Zhao P, Pan B, Gao J, Lv X, Wang Y, and Liu J. Advanced glycated end-products modified transferrin mediates oxidative stress and ferroptosis in podocytes via advanced glycation end-product receptor in vitro. Sci Rep. (2025) 15:39337. doi: 10.1038/s41598-025-22984-2

PubMed Abstract | Crossref Full Text | Google Scholar

134. Wang Y, Chen Q, Shi C, Jiao F, and Gong Z. Mechanism of glycyrrhizin on ferroptosis during acute liver failure by inhibiting oxidative stress. Mol Med Rep. (2019) 20:4081–90. doi: 10.3892/mmr.2019.10660

PubMed Abstract | Crossref Full Text | Google Scholar

135. Dai R, Qian Y, Liu S, Zou X, Sun S, and Sun Z. Growth arrest-specific 1 inhibits keap1/nrf2 signaling transduction in the activation of the ferroptosis program in retinal müller cells. Front Biosci (Landmark Ed). (2025) 30:27954. doi: 10.31083/FBL27954

PubMed Abstract | Crossref Full Text | Google Scholar

136. Liu D, Zheng Z, Chen Z, Guo R, Weng J, Huang S, et al. Ferroptosis in Müller cells under hyperglycemia: mechanisms and therapeutic implications for diabetic retinopathy-associated optic neuroinflammation. Int Ophthalmol. (2025) 45:302. doi: 10.1007/s10792-025-03681-5

PubMed Abstract | Crossref Full Text | Google Scholar

137. Li Y, Liu J, Ma X, and Bai X. Maresin-1 inhibits high glucose induced ferroptosis in ARPE-19 cells by activating the Nrf2/HO-1/GPX4 pathway. BMC Ophthalmol. (2023) 23:368. doi: 10.1186/s12886-023-03115-9

PubMed Abstract | Crossref Full Text | Google Scholar

138. Huang Y, Peng J, and Liang Q. Identification of key ferroptosis genes in diabetic retinopathy based on bioinformatics analysis. PloS One. (2023) 18:e0280548. doi: 10.1371/journal.pone.0280548

PubMed Abstract | Crossref Full Text | Google Scholar

139. Zhang X, Zhang Y, Wei J, Li X, Jiang A, Shen Y, et al. The role of SLC7A11 in tumor progression and the regulation mechanisms involved in ferroptosis. CMAR. (2025) 17:2393–401. doi: 10.2147/CMAR.S551549

PubMed Abstract | Crossref Full Text | Google Scholar

140. Lei M, Zhang Y, Huang F, Chen H, Chen M, Wu R, et al. Gankyrin inhibits ferroptosis through the p53/SLC7A11/GPX4 axis in triple-negative breast cancer cells. Sci Rep. (2023) 13:21916. doi: 10.1038/s41598-023-49136-8

PubMed Abstract | Crossref Full Text | Google Scholar

141. Kang R, Kroemer G, and Tang D. The tumor suppressor protein p53 and the ferroptosis network. Free Radical Biol Med. (2019) 133:162–8. doi: 10.1016/j.freeradbiomed.2018.05.074

PubMed Abstract | Crossref Full Text | Google Scholar

142. Ou Y, Wang SJ, Li D, Chu B, and Gu W. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci USA. (2016) 113:E6806–12. doi: 10.1073/pnas.1607152113

PubMed Abstract | Crossref Full Text | Google Scholar

143. Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. (2017) 20:1692–704. doi: 10.1016/j.celrep.2017.07.055

PubMed Abstract | Crossref Full Text | Google Scholar

144. Shimada K, Hayano M, Pagano NC, and Stockwell BR. Cell-line selectivity improves the predictive power of pharmacogenomic analyses and helps identify NADPH as biomarker for ferroptosis sensitivity. Cell Chem Biol. (2016) 23:225–35. doi: 10.1016/j.chembiol.2015.11.016

PubMed Abstract | Crossref Full Text | Google Scholar

145. Gray SP, Di Marco E, Okabe J, Szyndralewiez C, Heitz F, Montezano AC, et al. NADPH oxidase 1 plays a key role in diabetes mellitus–accelerated atherosclerosis. Circulation. (2013) 127:1888–902. doi: 10.1161/CIRCULATIONAHA.112.132159

PubMed Abstract | Crossref Full Text | Google Scholar

146. Ding C, Rose J, Sun T, Wu J, Chen P, Lin C, et al. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat Metab. (2020) 2:270–7. doi: 10.1038/s42255-020-0181-1

PubMed Abstract | Crossref Full Text | Google Scholar

147. Yan H, Zou T, Tuo Q, Xu S, Li H, Belaidi AA, et al. Ferroptosis: mechanisms and links with diseases. Sig Transduct Target Ther. (2021) 6:49. doi: 10.1038/s41392-020-00428-9

PubMed Abstract | Crossref Full Text | Google Scholar

148. Wang Y, Bi R, Quan F, Cao Q, Lin Y, Yue C, et al. Ferroptosis involves in renal tubular cell death in diabetic nephropathy. Eur J Pharmacol. (2020) 888:173574. doi: 10.1016/j.ejphar.2020.173574

PubMed Abstract | Crossref Full Text | Google Scholar

149. Omae T, Ono S, Kamiya T, Otani S, Yokota H, and Nagaoka T. Dipeptidyl peptidase 4, a novel adipokine, impairs retinal microcirculation in patients with type 2 diabetes mellitus. Invest Ophthalmol Vis Sci. (2025) 66:4. doi: 10.1167/iovs.66.14.4

PubMed Abstract | Crossref Full Text | Google Scholar

150. Singh LP, Yumnamcha T, and Devi TS. Mitophagy, ferritinophagy and ferroptosis in retinal pigment epithelial cells under high glucose conditions: implications for diabetic retinopathy and age-related retinal diseases. JOJ Ophthalmol. (2021) 8:77–85.

PubMed Abstract | Google Scholar

151. Li CH, Shyu MK, Jhan C, Cheng YW, Tsai CH, Liu CW, et al. Gold nanoparticles increase endothelial paracellular permeability by altering components of endothelial tight junctions, and increase blood-brain barrier permeability in mice. Toxicol Sci. (2015) 148:192–203. doi: 10.1093/toxsci/kfv176

PubMed Abstract | Crossref Full Text | Google Scholar

152. de Lima TM, Nery LEM, Maciel FE, Ngo-Vu H, Kozma MT, Derby CD, et al. Oxygen sensing in crustaceans: functions and mechanisms. J Comp Physiol A. (2021) 207:1–15. doi: 10.1007/s00359-020-01457-z

PubMed Abstract | Crossref Full Text | Google Scholar

153. Haase VH. Therapeutic targeting of the HIF oxygen-sensing pathway: Lessons learned from clinical studies. Exp Cell Res. (2017) 356:160–5. doi: 10.1016/j.yexcr.2017.05.004

PubMed Abstract | Crossref Full Text | Google Scholar

154. Chan TC, Wilkinson Berka JL, Deliyanti D, Hunter D, Fung A, Liew G, et al. The role of reactive oxygen species in the pathogenesis and treatment of retinal diseases. Exp Eye Res. (2020) 201:108255. doi: 10.1016/j.exer.2020.108255

PubMed Abstract | Crossref Full Text | Google Scholar

155. Wenger RH. Cellular adaptation to hypoxia: O₂ -sensing protein hydroxylases, hypoxia-inducible transcription factors, and O₂ -regulated gene expression. FASEB J. (2002) 16:1151–62. doi: 10.1096/fj.01-0944rev

PubMed Abstract | Crossref Full Text | Google Scholar

156. Fujii J and Imai H. Oxidative metabolism as a cause of lipid peroxidation in the execution of ferroptosis. IJMS. (2024) 25:7544. doi: 10.3390/ijms25147544

PubMed Abstract | Crossref Full Text | Google Scholar

157. Mimura T and Noma H. Oxidative stress in diabetic retinopathy: A comprehensive review of mechanisms, biomarkers, and therapeutic perspectives. Antioxidants. (2025) 14:1204. doi: 10.3390/antiox14101204

PubMed Abstract | Crossref Full Text | Google Scholar

158. Lee JJ, Ishihara K, Notomi S, Efstathiou NE, Ueta T, Maidana D, et al. Lysosome-associated membrane protein-2 deficiency increases the risk of reactive oxygen species-induced ferroptosis in retinal pigment epithelial cells. Biochem Biophys Res Commun. (2020) 521:414–9. doi: 10.1016/j.bbrc.2019.10.138

PubMed Abstract | Crossref Full Text | Google Scholar

159. Yumnamcha T, Devi TS, and Singh LP. Auranofin mediates mitochondrial dysregulation and inflammatory cell death in human retinal pigment epithelial cells: implications of retinal neurodegenerative diseases. Front Neurosci. (2019) 13:1065. doi: 10.3389/fnins.2019.01065

PubMed Abstract | Crossref Full Text | Google Scholar

160. Lu C, Lan Q, Song Q, and Yu X. Identification and validation of ferroptosis-related genes for diabetic retinopathy. Cell Signalling. (2024) 113:110955. doi: 10.1016/j.cellsig.2023.110955

PubMed Abstract | Crossref Full Text | Google Scholar

161. Totsuka K, Ueta T, Uchida T, Roggia MF, Nakagawa S, Vavvas DG, et al. Oxidative stress induces ferroptotic cell death in retinal pigment epithelial cells. Exp Eye Res. (2019) 181:316–24. doi: 10.1016/j.exer.2018.08.019

PubMed Abstract | Crossref Full Text | Google Scholar

162. Wang H and Tao Y. Choroidal structural changes correlate with severity of diabetic retinopathy in diabetes mellitus. BMC Ophthalmol. (2019) 19:186. doi: 10.1186/s12886-019-1189-8

PubMed Abstract | Crossref Full Text | Google Scholar

163. Valença A, Mendes-Jorge L, Bonet A, Catita J, Ramos D, Jose-Cunilleras E, et al. TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown. Exp Eye Res. (2021) 202:108292. doi: 10.1016/j.exer.2020.108292

PubMed Abstract | Crossref Full Text | Google Scholar

164. Chaudhary K, Promsote W, Ananth S, Veeranan-Karmegam R, Tawfik A, Arjunan P, et al. Iron overload accelerates the progression of diabetic retinopathy in association with increased retinal renin expression. Sci Rep. (2018) 8:3025. doi: 10.1038/s41598-018-21276-2

PubMed Abstract | Crossref Full Text | Google Scholar

165. Shen H, Gong Q, Zhang J, Wang H, and Qiu Q. TRIM46 aggravated high glucose-induced hyper permeability and inflammatory response in human retinal capillary endothelial cells by promoting IκBα ubiquitination. Eye Vis. (2022) 9:35. doi: 10.1186/s40662-022-00305-2

PubMed Abstract | Crossref Full Text | Google Scholar

166. Huang H. Pericyte-endothelial interactions in the retinal microvasculature. IJMS. (2020) 21:7413. doi: 10.3390/ijms21197413

PubMed Abstract | Crossref Full Text | Google Scholar

167. Chen X, Wang Y, Wang J, Cao Q, Sun R, Zhu H, et al. m6A modification of circSPECC1 suppresses RPE oxidative damage and maintains retinal homeostasis. Cell Rep. (2022) 41:111671. doi: 10.1016/j.celrep.2022.111671

PubMed Abstract | Crossref Full Text | Google Scholar

168. Zhang G, Yu J, and Wan Y. USP48 deubiquitination stabilizes SLC1A5 to inhibit retinal pigment epithelium cell inflammation, oxidative stress and ferroptosis in the progression of diabetic retinopathy. J Bioenerg Biomembr. (2024) 56:311–21. doi: 10.1007/s10863-024-10008-z

PubMed Abstract | Crossref Full Text | Google Scholar

169. 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

170. Dowdle WE, Nyfeler B, Nagel J, Elling RA, Liu S, Triantafellow E, et al. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis. vivo Nat Cell Biol. (2014) 16:1069–79. doi: 10.1038/ncb3053

PubMed Abstract | Crossref Full Text | Google Scholar

171. 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

172. Gao M, Monian P, Pan Q, Zhang W, Xiang J, and Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. (2016) 26:1021–32. doi: 10.1038/cr.2016.95

PubMed Abstract | Crossref Full Text | Google Scholar

173. Ma S, Dielschneider RF, Henson ES, Xiao W, Choquette TR, Blankstein AR, et al. Ferroptosis and autophagy induced cell death occur independently after siramesine and lapatinib treatment in breast cancer cells. PloS One. (2017) 12:e0182921. doi: 10.1371/journal.pone.0182921

PubMed Abstract | Crossref Full Text | Google Scholar

174. Yu F, Wang C, Su Y, Chen T, Zhu W, Dong X, et al. Comprehensive analysis of ferritinophagy-related genes and immune infiltration landscape in diabetic retinopathy. Front Endocrinol. (2023) 14:1177488. doi: 10.3389/fendo.2023.1177488

PubMed Abstract | Crossref Full Text | Google Scholar

175. Basit F, van Oppen LM, Schöckel L, Bossenbroek HM, van Emst-de Vries SE, Hermeling JC, et al. Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death Dis. (2017) 8:e2716–6. doi: 10.1038/cddis.2017.133

PubMed Abstract | Crossref Full Text | Google Scholar

176. Liao Y, Xu J, Qin B, Shi J, Qin C, Xie F, et al. Advanced oxidation protein products impair autophagic flux in macrophage by inducing lysosomal dysfunction via activation of PI3K-Akt-mTOR pathway in Crohn’s disease. Free Radical Biol Med. (2021) 172:33–47. doi: 10.1016/j.freeradbiomed.2021.05.018

PubMed Abstract | Crossref Full Text | Google Scholar

177. Linsenmeier RA and Zhang HF. Retinal oxygen: from animals to humans. Prog Retinal Eye Res. (2017) 58:115–51. doi: 10.1016/j.preteyeres.2017.01.003

PubMed Abstract | Crossref Full Text | Google Scholar

178. Zhang J, Qiu Q, Wang H, Chen C, and Luo D. TRIM46 contributes to high glucose-induced ferroptosis and cell growth inhibition in human retinal capillary endothelial cells by facilitating GPX4 ubiquitination. Exp Cell Res. (2021) 407:112800. doi: 10.1016/j.yexcr.2021.112800

PubMed Abstract | Crossref Full Text | Google Scholar

179. Liu C, Sun W, Zhu T, Shi S, Zhang J, Wang J, et al. Glia maturation factor-β induces ferroptosis by impairing chaperone-mediated autophagic degradation of ACSL4 in early diabetic retinopathy. Redox Biol. (2022) 52:102292. doi: 10.1016/j.redox.2022.102292

PubMed Abstract | Crossref Full Text | Google Scholar

180. Wu MY, Yiang GT, Lai TT, and Li CJ. The oxidative stress and mitochondrial dysfunction during the pathogenesis of diabetic retinopathy. Oxid Med Cell Longevity. (2018) 2018:3420187. doi: 10.1155/2018/3420187

PubMed Abstract | Crossref Full Text | Google Scholar

181. Farnoodian M, Halbach C, Slinger C, Pattnaik BR, Sorenson CM, and Sheibani N. High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression. Am J Physiology-Cell Physiol. (2016) 311:C418–36. doi: 10.1152/ajpcell.00001.2016

PubMed Abstract | Crossref Full Text | Google Scholar

182. Li S, Zhao N, Wei D, Pu N, Hao X, Huang J, et al. Ferroptosis in the ageing retina: A malevolent fire of diabetic retinopathy. Ageing Res Rev. (2024) 93:102142. doi: 10.1016/j.arr.2023.102142

PubMed Abstract | Crossref Full Text | Google Scholar

183. Sui Y, Zhang C, Jiang B, Li W, and Wang S. Tectochrysin alleviates high-glucose-induced retinal pigment epithelial cell injury through Nrf2/HO-1 activation. Folia Histochem Cytobiol. (2025) 63:134–41. doi: 10.5603/fhc.107923

PubMed Abstract | Crossref Full Text | Google Scholar

184. Li M, Tian M, Wang Y, Ma H, Zhou Y, Jiang X, et al. Updates on RPE cell damage in diabetic retinopathy (Review). Mol Med Rep. (2023) 28:185. doi: 10.3892/mmr.2023.13072

PubMed Abstract | Crossref Full Text | Google Scholar

185. Xi X, Chen Q, Ma J, Wang X, Zhang J, Li Y, et al. Sestrin2 ameliorates diabetic retinopathy by regulating autophagy and ferroptosis. J Mol Histol. (2024) 55:169–84. doi: 10.1007/s10735-023-10180-3

PubMed Abstract | Crossref Full Text | Google Scholar

186. Tang X, Li X, Zhang D, and Han W. Astragaloside-IV alleviates high glucose-induced ferroptosis in retinal pigment epithelial cells by disrupting the expression of miR-138-5p/Sirt1/Nrf2. Bioengineered. (2022) 13:8238–53. doi: 10.1080/21655979.2022.2049471

PubMed Abstract | Crossref Full Text | Google Scholar

187. Truong Do M, Gyun Kim H, Ho Choi J, and Gwang Jeong H. Metformin induces microRNA-34a to downregulate the Sirt1/Pgc-1α/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents. Free Radical Biol Med. (2014) 74:21–34. doi: 10.1016/j.freeradbiomed.2014.06.010

PubMed Abstract | Crossref Full Text | Google Scholar

188. Ma F, Wu J, Jiang Z, Huang W, Jia Y, Sun W, et al. P53/NRF2 mediates SIRT1’s protective effect on diabetic nephropathy. Biochim Biophys Acta (BBA) - Mol Cell Res. (2019) 1866:1272–81. doi: 10.1016/j.bbamcr.2019.04.006

PubMed Abstract | Crossref Full Text | Google Scholar

189. Chen J, Lai J, Yang L, Ruan G, Chaugai S, Ning Q, et al. Trimetazidine prevents macrophage-mediated septic myocardial dysfunction via activation of the histone deacetylase sirtuin 1. Br J Pharmacol. (2016) 173:545–61. doi: 10.1111/bph.13386

PubMed Abstract | Crossref Full Text | Google Scholar

190. Arioz BI, Tastan B, Tarakcioglu E, Tufekci KU, Olcum M, Ersoy N, et al. Melatonin attenuates LPS-induced acute depressive-like behaviors and microglial NLRP3 inflammasome activation through the SIRT1/nrf2 pathway. Front Immunol. (2019) 10:1511. doi: 10.3389/fimmu.2019.01511

PubMed Abstract | Crossref Full Text | Google Scholar

191. Zhu H, Yang H, Zhao S, Zhang J, Liu D, Tian Y, et al. Role of the cofilin 2 gene in regulating the myosin heavy chain genes in mouse myoblast C2C12 cells. Int J Mol Med. (2018) 41:1096–102. doi: 10.3892/ijmm.2017.3272

PubMed Abstract | Crossref Full Text | Google Scholar

192. Thirion C, Stucka R, Mendel B, Gruhler A, Jaksch M, Nowak KJ, et al. Characterization of human muscle type cofilin (CFL2) in normal and regenerating muscle. Eur J Biochem. (2001) 268:3473–82. doi: 10.1046/j.1432-1327.2001.02247.x

PubMed Abstract | Crossref Full Text | Google Scholar

193. Zhu Z, Duan P, Song H, Zhou R, and Chen T. Downregulation of Circular RNA PSEN1 ameliorates ferroptosis of the high glucose treated retinal pigment epithelial cells via miR-200b-3p/cofilin-2 axis. Bioengineered. (2021) 12:12555–67. doi: 10.1080/21655979.2021.2010369

PubMed Abstract | Crossref Full Text | Google Scholar

194. Cui J, Shu C, Xu J, Chen D, Li J, Ding K, et al. JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling. Theranostics. (2020) 10:8036–50. doi: 10.7150/thno.45843

PubMed Abstract | Crossref Full Text | Google Scholar

195. Zhao L, Xu H, Liu X, Cheng Y, and Xie J. The role of TET2-mediated ROBO4 hypomethylation in the development of diabetic retinopathy. J Transl Med. (2023) 21:455. doi: 10.1186/s12967-023-04310-4

PubMed Abstract | Crossref Full Text | Google Scholar

196. Radhakrishnan R and Kowluru RA. 198Long noncoding RNA MALAT1 and regulation of the antioxidant defense system in diabetic retinopathy. Diabetes. (2021) 70:227–39. doi: 10.2337/db20-0375

PubMed Abstract | Crossref Full Text | Google Scholar

197. Barber AJ. A new view of diabetic retinopathy: a neurodegenerative disease of the eye. Prog Neuropsychopharmacol Biol Psychiatry. (2003) 27:283–90. doi: 10.1016/S0278-5846(03)00023-X

PubMed Abstract | Crossref Full Text | Google Scholar

198. Villarroel M. Neurodegeneration: An early event of diabetic retinopathy. WJD. (2010) 1:57. doi: 10.4239/wjd.v1.i2.57

PubMed Abstract | Crossref Full Text | Google Scholar

199. Forrester JV, Kuffova L, and Delibegovic M. The role of inflammation in diabetic retinopathy. Front Immunol. (2020) 11:583687. doi: 10.3389/fimmu.2020.583687

PubMed Abstract | Crossref Full Text | Google Scholar

200. Ayten M, Straub T, Kaplan L, Hauck SM, Grosche A, Koch SF, et al. CD44 signaling in Müller cells impacts photoreceptor function and survival in healthy and diseased retinas. J Neuroinflammation. (2024) 21:190. doi: 10.1186/s12974-024-03175-8

PubMed Abstract | Crossref Full Text | Google Scholar

201. Rosato C, Bettegazzi B, Intagliata P, Balbontin Arenas M, Zacchetti D, Lanati A, et al. Redox and calcium alterations of a müller cell line exposed to diabetic retinopathy-like environment. Front Cell Neurosci. (2022) 16:862325. doi: 10.3389/fncel.2022.862325

PubMed Abstract | Crossref Full Text | Google Scholar

202. Li Z, Xiong Q, Li Q, and Tang L. Parthenolide ameliorates diabetic retinopathy by suppressing microglia-induced Müller cell gliosis and inflammation via the NF-κB signalling. Int Immunopharmacol. (2025) 151:114219. doi: 10.1016/j.intimp.2025.114219

PubMed Abstract | Crossref Full Text | Google Scholar

203. Gong Q, Wang J, Luo D, Xu Y, Zhang R, Li X, et al. Accumulation of branched-chain amino acids deteriorates the neuroinflammatory response of Müller cells in diabetic retinopathy via leucine/Sestrin2-mediated sensing of mTOR signaling. Acta Diabetol. (2024) 62:227–40. doi: 10.1007/s00592-024-02349-3

PubMed Abstract | Crossref Full Text | Google Scholar

204. Hu X, Xu M, Zhou H, Cheng S, Li F, Miao Y, et al. Tumor necrosis factor-alpha aggravates gliosis and inflammation of activated retinal Müller cells. Biochem Biophys Res Commun. (2020) 531:383–9. doi: 10.1016/j.bbrc.2020.07.102

PubMed Abstract | Crossref Full Text | Google Scholar

205. McCarthy RC, Sosa JC, Gardeck AM, Baez AS, Lee CH, and Wessling-Resnick M. Inflammation-induced iron transport and metabolism by brain microglia. J Biol Chem. (2018) 293:7853–63. doi: 10.1074/jbc.RA118.001949

PubMed Abstract | Crossref Full Text | Google Scholar

206. Galaris D, Barbouti A, and Pantopoulos K. Iron homeostasis and oxidative stress: An intimate relationship. Biochim Biophys Acta (BBA) - Mol Cell Res. (2019) 1866:118535. doi: 10.1016/j.bbamcr.2019.118535

PubMed Abstract | Crossref Full Text | Google Scholar

207. 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) 172:409–422.e21. doi: 10.1016/j.cell.2017.11.048

PubMed Abstract | Crossref Full Text | Google Scholar

208. Chen P, Huang X, Wen W, Cao Y, Li W, Huang G, et al. MiR214-3p ameliorates diabetic cardiomyopathy by inhibiting ferroptosis. Cardiovasc Toxicol. (2025) 25:884–97. doi: 10.1007/s12012-025-09992-4

PubMed Abstract | Crossref Full Text | Google Scholar

209. Liu C, Liu X, Ouyang P, Liu Q, Huang X, Xiao F, et al. Ferrostatin-1 attenuates pathological angiogenesis in oxygen-induced retinopathy via inhibition of ferroptosis. Exp Eye Res. (2023) 226:109347. doi: 10.1016/j.exer.2022.109347

PubMed Abstract | Crossref Full Text | Google Scholar

210. Kusunose N, Akamine T, Kobayashi Y, Yoshida S, Kimoto K, Yasukochi S, et al. Contribution of the clock gene DEC2 to VEGF mRNA upregulation by modulation of HIF1α protein levels in hypoxic MIO-M1 cells, a human cell line of retinal glial (Müller) cells. Jpn J Ophthalmol. (2018) 62:677–85. doi: 10.1007/s10384-018-0622-5

PubMed Abstract | Crossref Full Text | Google Scholar

211. Wang L, Liu Y, Du T, Yang H, Lei L, Guo M, et al. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc–. Cell Death Differ. (2020) 27:662–75. doi: 10.1038/s41418-019-0380-z

PubMed Abstract | Crossref Full Text | Google Scholar

212. Chen Z, Liu B, Zhou D, Lei M, Yang J, Hu Z, et al. AQP4 regulates ferroptosis and oxidative stress of Muller cells in diabetic retinopathy by regulating TRPV4. Exp Cell Res. (2024) 439:114087. doi: 10.1016/j.yexcr.2024.114087

PubMed Abstract | Crossref Full Text | Google Scholar

213. Gui F, You Z, Fu S, Wu H, and Zhang Y. Endothelial dysfunction in diabetic retinopathy. Front Endocrinol. (2020) 11:591. doi: 10.3389/fendo.2020.00591

PubMed Abstract | Crossref Full Text | Google Scholar

214. Giacco F and Brownlee M. Oxidative stress and diabetic complications. Schmidt AM Ed Circ Res. (2010) 107:1058–70. doi: 10.1161/CIRCRESAHA.110.223545

PubMed Abstract | Crossref Full Text | Google Scholar

215. Stitt AW. The role of advanced glycation in the pathogenesis of diabetic retinopathy. Exp Mol Pathology. (2003) 75:95–108. doi: 10.1016/S0014-4800(03)00035-2

PubMed Abstract | Crossref Full Text | Google Scholar

216. Xie H, Guo J, Yang M, and Wang J. Kinase PIM1 governs ferroptosis to reduce retinal microvascular endothelial cell dysfunction triggered by high glucose. In Vitro CellDevBiol-Animal. (2024) 60:278–86. doi: 10.1007/s11626-024-00882-7

PubMed Abstract | Crossref Full Text | Google Scholar

217. Kang Q and Yang C. Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Redox Biol. (2020) 37:101799. doi: 10.1016/j.redox.2020.101799

PubMed Abstract | Crossref Full Text | Google Scholar

218. Zheng D, Liu J, Piao H, Zhu Z, Wei R, and Liu K. ROS-triggered endothelial cell death mechanisms: Focus on pyroptosis, parthanatos, and ferroptosis. Front Immunol. (2022) 13:1039241. doi: 10.3389/fimmu.2022.1039241

PubMed Abstract | Crossref Full Text | Google Scholar

219. Harrison AV, Lorenzo FR, and McClain DA. Iron and the pathophysiology of diabetes. Annu Rev Physiol. (2023) 85:339–62. doi: 10.1146/annurev-physiol-022522-102832

PubMed Abstract | Crossref Full Text | Google Scholar

220. Liu Q, Liu C, Yi W, Ouyang P, Yang B, Liu Q, et al. Ferroptosis contributes to microvascular dysfunction in diabetic retinopathy. Am J Pathology. (2024) 194:1078–89. doi: 10.1016/j.ajpath.2024.01.019

PubMed Abstract | Crossref Full Text | Google Scholar

221. Chen J, Peng W, Yang W, You Z, and Zou Y. Berberine inhibits high glucose-induced ferroptosis in retinal vascular endothelial cells: Mechanism and implications. Exp Eye Res. (2025) 259:110531. doi: 10.1016/j.exer.2025.110531

PubMed Abstract | Crossref Full Text | Google Scholar

222. Li S, Lu S, Wang L, Liu S, Zhang L, Du J, et al. Effects of amygdalin on ferroptosis and oxidative stress in diabetic retinopathy progression via the NRF2/ARE signaling pathway. Exp Eye Res. (2023) 234:109569. doi: 10.1016/j.exer.2023.109569

PubMed Abstract | Crossref Full Text | Google Scholar

223. Yang Z, Yan Y, Wang L, Zou G, and Lu L. PCBP1 modulates cellular iron homeostasis via targeting HIF-1α/HO-1 pathway and alleviates high-glucose-induced ferroptosis in HRMECs. Exp Eye Res. (2025) 259:110576. doi: 10.1016/j.exer.2025.110576

PubMed Abstract | Crossref Full Text | Google Scholar

224. Zhan D, Zhao J, Shi Q, Lou J, and Wang W. 25-hydroxyvitamin D3 inhibits oxidative stress and ferroptosis in retinal microvascular endothelial cells induced by high glucose through down-regulation of miR-93. BMC Ophthalmol. (2023) 23:22. doi: 10.1186/s12886-022-02762-8

PubMed Abstract | Crossref Full Text | Google Scholar

225. Liu Z, Gan S, Fu L, Xu Y, Wang S, Zhang G, et al. 1,8-Cineole ameliorates diabetic retinopathy by inhibiting retinal pigment epithelium ferroptosis via PPAR-γ/TXNIP pathways. Biomedicine Pharmacotherapy. (2023) 164:114978. doi: 10.1016/j.biopha.2023.114978

PubMed Abstract | Crossref Full Text | Google Scholar

226. Song Y, Lv P, and Yu J. Platycodin D inhibits diabetic retinopathy via suppressing TLR4 / MyD88 / NF-κB signaling pathway and activating Nrf2/ HO -1 signaling pathway. Chem Biol Drug Des. (2024) 103:e14419. doi: 10.1111/cbdd.14419

PubMed Abstract | Crossref Full Text | Google Scholar

227. Cai Y, Peng S, Duan B, Shao Y, Li X, Zou H, et al. Isoquercetin alleviates diabetic retinopathy via inhibiting p53-mediated ferroptosis. Cell Biol Int. (2025) 49:852–64. doi: 10.1002/cbin.70027

PubMed Abstract | Crossref Full Text | Google Scholar

228. Huang D, Shi G, Jiang Y, Yao C, and Zhu C. A review on the potential of Resveratrol in prevention and therapy of diabetes and diabetic complications. BioMed Pharmacother. (2020) 125:109767. doi: 10.1016/j.biopha.2019.109767

PubMed Abstract | Crossref Full Text | Google Scholar

229. Kaštelan S, Konjevoda S, Saric A, Urlic I, Lovric I, Canovic S, et al. Resveratrol as a novel therapeutic approach for diabetic retinopathy: molecular mechanisms, clinical potential, and future challenges. Molecules. (2025) 30:3262. doi: 10.3390/molecules30153262

PubMed Abstract | Crossref Full Text | Google Scholar

230. Ren J, Zhang S, Pan Y, Jin M, Li J, Luo Y, et al. Diabetic retinopathy: Involved cells, biomarkers, and treatments. Front Pharmacol. (2022) 13:953691. doi: 10.3389/fphar.2022.953691

PubMed Abstract | Crossref Full Text | Google Scholar

231. Tang W, Guo J, Liu W, Ma J, and Xu G. Ferrostatin-1 attenuates ferroptosis and protects the retina against light-induced retinal degeneration. Biochem Biophys Res Commun. (2021) 548:27–34. doi: 10.1016/j.bbrc.2021.02.055

PubMed Abstract | Crossref Full Text | Google Scholar

232. Guo M, Zhu Y, Shi Y, Meng X, Dong X, Zhang H, et al. Inhibition of ferroptosis promotes retina ganglion cell survival in experimental optic neuropathies. Redox Biol. (2022) 58:102541. doi: 10.1016/j.redox.2022.102541

PubMed Abstract | Crossref Full Text | Google Scholar

233. Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc. (2014) 136:4551–6. doi: 10.1021/ja411006a

PubMed Abstract | Crossref Full Text | Google Scholar

234. Feng W, Xiao Y, Zhao C, Zhang Z, Liu W, Ma J, et al. New deferric amine compounds efficiently chelate excess iron to treat iron overload disorders and to prevent ferroptosis. Advanced Science. (2022) 9:2202679. doi: 10.1002/advs.202202679

PubMed Abstract | Crossref Full Text | Google Scholar

235. Tang L, Zhao C, Ren Y, Liang H, and Zhang M. Elucidating programmed cell death in diabetic retinal microangionopathy and neurodegeneration: unraveling molecular mechanisms and therapeutic actions of natural products. Inflammopharmacol. (2025) 33:3755–88. doi: 10.1007/s10787-025-01840-9

PubMed Abstract | Crossref Full Text | Google Scholar

236. Gómez-Jiménez V, Burggraaf-Sánchez De Las Matas R, and Ortega ÁL. Modulation of oxidative stress in diabetic retinopathy: therapeutic role of natural polyphenols. Antioxidants. (2025) 14:875. doi: 10.3390/antiox14070875

PubMed Abstract | Crossref Full Text | Google Scholar

237. Xie Y, Li C, Dong X, Wang B, Qin J, Lv H, et al. Natural products as modulators of iron metabolism and ferroptosis in diabetes and its complications. Nutrients. (2025) 17:2714. doi: 10.3390/nu17162714

PubMed Abstract | Crossref Full Text | Google Scholar