Epidermal growth factor receptor modulation for neural repair: Implications for neurodegenerative disease therapy

Abstract

The epidermal growth factor receptor (EGFR; ErbB1/HER1) is a receptor tyrosine kinase that regulates cell proliferation, survival, differentiation, and tissue repair. In the nervous system, EGFR is expressed in neural progenitors, astrocytes, oligodendrocyte precursor cells, and neuronal populations, where its functions are context dependent. EGFR signaling contributes to neural regeneration by promoting progenitor proliferation, neuronal survival, neurogenesis, and remyelination following injury. However, sustained or excessive EGFR activation can drive reactive astrogliosis, neuroinflammation, glial scar formation, and neurotoxicity. Emerging evidence suggests that transient, regulated EGFR activation supports neural repair, whereas chronic or dysregulated signaling may contribute to neurodegeneration. These apparently opposing effects likely reflect differences in timing, duration, cellular context, ligand availability, and downstream signaling pathways engaged by EGFR activation, rather than inherently contradictory biological functions. In experimental models of Parkinson’s disease, Alzheimer’s disease, and Multiple sclerosis-like conditions, EGFR modulation has shown therapeutic potential, although the mechanisms remain incompletely understood. While EGFR ligands often exert neurotrophic and pro-remyelinating effects, disease-associated EGFR activation may promote maladaptive signaling pathways. In this review, we summarize current knowledge of EGFR signaling in neural repair and neurodegenerative diseases, discuss the context-dependent roles of this pathway, and highlight therapeutic strategies. We further propose a conceptual framework in which EGFR functions as a context-dependent signaling hub, with its outcomes determined by the spatiotemporal regulation of receptor activation. Although challenges remain, including optimal timing, dosing, and safety considerations, preclinical evidence suggests that modulation of EGFR signaling may be a therapeutic approach to promote neural repair while limiting neurodegenerative pathology.

Graphical Abstract

1 Introduction

1.1 EGFR signaling in the nervous system

The epidermal growth factor receptor (EGFR, also known as ErbB1/HER1) is a transmembrane receptor tyrosine kinase of the ErbB family that regulates cell proliferation, survival, migration, and differentiation (Cohen et al., 1980; Shaban et al., 2023). EGFR is activated by several ligands, including epidermal growth factor (EGF), transforming growth factor-α (TGF-α), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN), which are released from membrane-bound precursors mainly through ADAM10/17-mediated proteolytic cleavage (Adrain and Badenes, 2024; Duffy et al., 2011; Rosenbaum and Saftig, 2024), (Saad and Jenkins, 2024). Ligand binding induces EGFR homo- or heterodimerization with other ErbB receptors, activating downstream signaling pathways including RAS/RAF/MEK/ERK–MAPK, PI3K/AKT/mTOR, PLCγ/PKC, SRC, JNK, and JAK/STAT cascades, which collectively regulate diverse cellular functions in the nervous system (Rosenkranz and Slastnikova, 2020, Romano and Bucci, 2020; Figure 1). These pathways are involved in neuronal repair and in the pathobiology of several neurodegenerative diseases, as summarized in Tables 1, 2, respectively. The biological outcome of EGFR activation is determined by multiple factors, including ligand availability, signal intensity and duration, receptor dimerization partners, and the responding cell type. Consequently, EGFR signaling can support either tissue repair or pathological remodeling depending on the physiological or disease context. This context-dependent nature of EGFR signaling provides the central framework of this review and offers a mechanistic basis for understanding why both EGFR activation and inhibition have produced beneficial effects in different experimental models of neurological disease.

Figure 1

EGFR is expressed in both the central and peripheral nervous systems, particularly during development, and EGFR-deficient mice exhibit multiple neural abnormalities (Sibilia et al., 1998; Kornblum et al., 1998). In the adult brain, EGFR signaling plays important roles in neural stem and progenitor cell proliferation, neurogenesis, neurite outgrowth, astrocyte activation, and remyelination. EGF and TGF-α promote neural progenitor proliferation and neuronal survival, while HB-EGF and BTC enhance neurogenesis and neural precursor survival (Doetsch et al., 2002; Bath and Lee, 2010; Getchell et al., 2000). EGFR signaling in neural stem cell niches regulates progenitor expansion and differentiation, although prolonged activation may skew differentiation toward astrocytic or oligodendroglial lineages at the expense of neurons (Kuhn et al., 1997; Gonzalez-Perez et al., 2009). These findings suggest that tightly regulated EGFR signaling is required to maintain a balance between stem cell renewal and lineage commitment within the adult nervous system. Notably, the downstream biological response is influenced not only by receptor activation itself but also by the specific ligand involved, the composition of ErbB receptor dimers, and the intracellular signaling pathways preferentially engaged.

In neurons and astrocytes, EGFR signaling can promote neurite extension, neuronal survival, and the formation of a pro-regenerative environment, largely through AKT and ERK signaling pathways (Goldshmit et al., 2004a; Goldshmit et al., 2004b; Liu and Neufeld, 2004). However, sustained EGFR activation may also promote reactive astrogliosis, neuroinflammation, and glial scar formation, highlighting the context-dependent nature of EGFR signaling in the nervous system (Liu et al., 2006; Romano and Bucci, 2020; Badenes, 2024; Qu et al., 2012). A growing body of evidence indicates that transient EGFR activation following injury often promotes regenerative processes, whereas chronic or excessive activation, particularly in reactive glial populations, may drive inflammatory and neurodegenerative responses. This apparent functional dichotomy may explain why both EGFR agonists and inhibitors have shown beneficial effects in different experimental models of neurological disease. Importantly, these seemingly opposing findings should not be viewed as contradictory but rather as reflecting the highly dynamic and spatiotemporally regulated nature of EGFR signaling within the injured or diseased nervous system. In demyelinating conditions, reactivation of EGFR signaling in oligodendrocyte lineage cells enhances oligodendrogenesis and remyelination (Aguirre et al. (2007); Scafidi et al., 2014; Bartus et al., 2019). Overall, EGFR signaling exerts complex and highly cell-type-dependent effects in the nervous system, contributing to both regenerative and pathological processes depending on the cellular and disease context. Understanding the factors that determine this switch between beneficial and detrimental EGFR signaling remains a major challenge and is central to the development of EGFR-targeted therapies for neurological disorders. Throughout this review, we examine the evidence supporting this context-dependent model and discuss how a better understanding of EGFR signaling dynamics may guide the development of more precise therapeutic strategies for neurodegenerative diseases.

1.2 EGFR in neural repair

EGFR signaling is rapidly activated following central nervous system (CNS) injury in glial cells and neural progenitors, where it contributes to tissue repair, neurogenesis, and cell survival (Liu et al., 2006; Romano and Bucci, 2020, Li Z.W. et al., 2021). However, EGFR signaling exerts highly context-dependent effects. Moderate and transient activation of EGFR can promote regeneration by enhancing neural progenitor proliferation, neuroblast migration, neurite outgrowth, and remyelination, whereas sustained or excessive activation often drives reactive astrogliosis, neuroinflammation, glial scar formation, and neurodegeneration (Liu and Neufeld, 2003; Qu et al., 2012; Li et al., 2014). These contrasting effects likely reflect differences in the timing, intensity, cellular localization, and duration of EGFR signaling following injury. In particular, ligand-driven activation of EGFR in neural progenitors and oligodendrocyte lineage cells generally promotes regenerative responses, whereas prolonged activation in reactive astrocytes and inflammatory cells may exacerbate tissue damage and impede recovery. These context-dependent effects are also likely influenced by selective engagement of downstream signaling pathways, with PI3K/AKT and ERK signaling generally associated with cell survival and regeneration, whereas sustained activation of inflammatory signaling pathways, including JAK/STAT, may contribute to reactive gliosis and chronic neuroinflammation. Consistent with this dual role, both EGFR activation and inhibition have shown beneficial effects across different injury models, depending on timing, cell type, and signaling context. Key findings are summarized in Table 3.

In models of traumatic brain injury and ischemic stroke, EGF promotes neural repair by enhancing progenitor proliferation, neurogenesis, and neuronal survival, particularly within the subventricular zone and hippocampus (Teramoto et al., 2003; Sun et al., 2010). Similarly, EGFR signaling contributes to oligodendrocyte progenitor expansion and remyelination following demyelinating injury (Aguirre et al., 2007). These findings support a role for transient EGFR activation in restoring neural cell populations and promoting functional recovery after injury. Conversely, excessive EGFR activation in reactive astrocytes has been associated with neurotoxicity, impaired neurogenesis, and inflammatory gliosis. Accordingly, pharmacological inhibition of EGFR has been shown to reduce astrocyte and microglial activation, enhance neuroblast migration, promote axonal regeneration, and improve functional recovery in several CNS injury models, including optic nerve injury, spinal cord injury, and subarachnoid hemorrhage (Koprivica et al., 2005; Erschbamer et al., 2007; Gómez-Oliva et al., 2023; Nakano et al., 2023). Collectively, these studies suggest that the therapeutic value of EGFR inhibition may arise from limiting maladaptive glial responses rather than suppressing regenerative EGFR signaling per se. Together, these findings emphasize that the biological outcome of EGFR modulation is determined less by whether the pathway is activated or inhibited, and more by when, where, and in which cell types the intervention occurs.

In spinal cord injury, EGFR signaling has been implicated in both regenerative and pathological processes. EGFR inhibition suppresses astrogliosis and glial scar formation, protects oligodendrocytes from apoptosis, and promotes neurogenesis and myelination (Qu et al. 2012; Li et al., 2014; Zhang et al., 2016). In contrast, some studies suggest that EGFR activation in astrocytes may support neurite outgrowth and tissue repair under specific conditions, while EGFR overexpression or delivery of EGFR-containing exosomes, HB-EGF, or EGF can improve recovery after spinal cord injury (White et al., 2011; Cigliola et al., 2023, Qin et al., 2024). At first glance, these findings appear contradictory. However, they may instead reflect distinct phases of the injury response. Early and controlled EGFR activation may facilitate cell survival, axonal growth, and tissue repair, whereas persistent EGFR activation during later stages may promote chronic gliosis and scar formation. Thus, the timing of intervention may be a critical determinant of whether EGFR activation or inhibition is therapeutically beneficial. Together, these findings suggest that the effects of EGFR signaling in neural repair are highly dependent on the magnitude, duration, and cellular localization of pathway activation. Future studies combining cell-type-specific genetic models with single-cell and spatial transcriptomic approaches will be important for defining the spatiotemporal dynamics of EGFR signaling during neural repair and for identifying therapeutic windows that maximize regeneration while minimizing pathological remodeling. A better understanding of the spatiotemporal regulation of EGFR signaling following CNS injury will be essential for developing therapeutic approaches that selectively enhance regenerative processes while minimizing pathological outcomes.

1.3 EGFR in neurodegenerative diseases

Alterations in EGFR expression and signaling have been implicated in multiple neurodegenerative diseases. Key findings are summarized in Table 4 and in Figure 2. However, the current evidence remains limited and, in some cases, conflicting. These inconsistencies likely reflect the complex and context-dependent nature of EGFR signaling, whereby physiological EGFR activity may support neuronal survival and tissue homeostasis, while chronic or dysregulated activation may contribute to neuroinflammation and neurodegeneration. Furthermore, much of the current evidence is derived from animal models and in vitro studies, highlighting the need for additional mechanistic and translational studies in humans. Importantly, the available evidence suggests that EGFR does not function as a universal driver of neurodegeneration, but rather as a context-dependent signaling node whose effects vary according to disease stage, cellular environment, and the mechanisms underlying individual neurodegenerative disorders.

Figure 2

1.3.1 Parkinson’s disease

In Parkinson’s disease (PD), patients’ brains show decreased EGF and EGFR levels (Iwakura and Nawa, 2013; Iwakura et al., 2005). Genetic PD models implicate EGFR trafficking: Parkin is mutated in an autosomal recessive form of PD, and its loss promotes EGFR internalization and degradation, reducing EGFR/AKT signaling in neurons (Husnjak and Dikic, 2006; Fallon et al., 2006); Leucine-rich repeat kinase 2 (LRRK2) mutations in PD similarly perturb EGFR recycling (Gómez-Suaga et al., 2014). These deficits in EGFR/AKT may contribute to dopaminergic neuron loss and PD progression, or can also be a consequence of dopaminergic neuron loss due to gene mutations or by other factors. Notably, EGFR inhibition with the tyrosine kinase inhibitor AZD3759 or lapatinib shows beneficial effect in rodents (Tavassoly et al., 2021; Mansour et al., 2024). AZD3759 reduces phosphorylated α-synuclein pathology, indicating that EGFR may facilitate pathological protein spread (Tavassoly et al., 2021). Lapatinib exerts antioxidant actions and restores dopaminergic neurons, improving motor impairment and histopathological abnormalities. This dopaminergic effect is mediated by the upregulation of dopamine D3 receptors, increased tyrosine hydroxylase expression, and elevated dopamine levels (Mansour et al., 2024). Importantly, the study by Mansour and colleagues utilized an acute toxin-induced model rather than a synucleinopathy model, and therefore may not fully capture the pathogenic mechanisms underlying human PD. Conversely, some data suggest EGFR activity is neuroprotective, as EGFR-mediated phosphorylation of chaperone DNAJB1 helps clear α-synuclein in Parkinson’s disease (Huang et al., 2025). Taken together, these findings suggest that physiological EGFR signaling may support neuronal maintenance and proteostatic homeostasis, whereas aberrant or sustained EGFR activation may contribute to pathological α-synuclein accumulation and neuroinflammation. This framework may help explain why both impaired EGFR signaling and EGFR inhibition have been reported to produce beneficial effects in distinct PD models, potentially reflecting context-dependent roles of EGFR signaling in disease progression. Whether these apparently opposing roles reflect differences in disease stage, cellular targets, or selective activation of downstream signaling pathways remains an important question for future investigation.

1.3.2 Alzheimer’s disease

In Alzheimer’s disease (AD), several studies report increased EGFR expression and activation in the brain (elevated EGFR phosphorylation) in amyloid precursor protein (APP)/ Presenilin 1 (PS1) mouse models, associated to increased amyloid beta (Aβ) neurotoxicity and possibly neuroinflammation by promoting astrocyte activation (Choi et al., 2023; Jayaswamy et al., 2023; Mansour et al., 2022; Ferrer et al., 1996; Birecree et al., 1988; Özbeyli et al., 2017). The EGFR ligands EGF and HB-EGF upregulate APP protein levels in neuronal cells, and interact with APP to boost ERK signaling and neurite outgrowth which is blocked by EGFR inhibition (da Rocha et al., 2021). Aβ binds to EGFR (Wang et al., 2012) and Aβ deposition elevates EGFR expression and induces sustained activation of EGFR and downstream signaling pathways (Jayaswamy et al., 2023; Wang et al., 2013; Kirouac et al., 2017). EGFR overexpression worsens memory deficits (Prüßing et al., 2013), while EGFR inhibitors ameliorate memory loss (Özbeyli et al., 2017; Wang et al., 2012). However, findings from Drosophila models should be interpreted cautiously, as species-specific differences in EGFR signaling and AD-related pathways may limit their direct translational relevance to human disease. Furthermore, EGFR inhibition may promote autophagy to clear aggregation of toxic amyloid structures (Tavassoly et al., 2020). Collectively, these studies support the notion that chronic EGFR activation contributes to AD pathology by promoting Aβ-mediated toxicity.

However, paradoxically, chronic EGF administration also prevents cognitive dysfunction in a mouse model (possibly by enhancing neurogenesis), despite it does not alter the brain levels of EGFR or Aβ (Thomas et al., 2016). This apparent discrepancy may reflect differences between ligand-mediated physiological EGFR activation and disease-associated receptor activation induced by Aβ accumulation. Whereas pathological EGFR activation appears to exacerbate neurodegeneration, controlled stimulation by endogenous ligands may promote neurogenesis, neuronal survival, or synaptic plasticity. Thus, the biological consequences of EGFR signaling in AD likely depend on both the source and duration of pathway activation. These observations further suggest that selectively modulating pathological EGFR activation while preserving its physiological neurotrophic functions may represent a more effective therapeutic strategy than indiscriminate inhibition of the pathway.

1.3.3 Amyotrophic lateral sclerosis

EGFR signaling may also affect amyotrophic lateral sclerosis (ALS) pathology, but data are limited. In ALS, EGF levels are reduced in the cerebrospinal fluid (Cieślak et al., 1986), but EGFR mRNA expression is elevated in spinal cords (Offen et al., 2009), while protein levels are unclear. EGFR inhibitor erlotinib in SOD1-G93A mice shows modest benefits, leading to delayed symptoms-onset, but not extending survival or rescuing neuromuscular synapses (Le Pichon et al., 2013). Overall, the currently available data are insufficient to establish a clear role for EGFR signaling in ALS pathogenesis, highlighting an important area for future investigation. Future studies should determine whether altered EGFR signaling contributes directly to motor neuron degeneration or represents a secondary response to ongoing neurodegeneration.

1.3.4 Multiple sclerosis

Several studies highlight EGFR pathway in remyelination in Multiple sclerosis (MS)-like models. In chemical-induced CNS demyelination model exogenous HB-EGF and EGF promote SVZ proliferation and mobilization and an increase in oligodendrocyte number in the lesion site (Gonzalez-Perez et al., 2009; Cantarella et al., 2008). In encephalomyelitis virus-induced CNS demyelination model high CNS EGF gene expression promotes repair (Bieber et al., 2010), while in myelin ODC glycoprotein (MOG)-induced experimental allergic encephalomyelitis (EAE), chronic treatment with EGF had a preventive effect leading to almost complete absence of signs of demyelination (Nicoletti et al., 2019). In another study, EGF co-administration with growth hormone releasing peptide-6, but not alone, improved the clinical score and survival rate of mild and severe EAE forms (Del Barco et al., 2011). Patients with MS have significantly lower EGF levels in the cerebrospinal fluid (Scalabrino et al., 2010) and in the spinal cord (Scalabrino et al., 2015), but no differences in the mRNA level in cortical lesions neither in chronic or chronic active plaques (Nicoletti et al., 2019). However, they have less EGFR gene expression in chronic active plaques (Nicoletti et al., 2019). Low plasma EGF levels are significantly reduced in the patients with progressive disease compared with those with relapsing remitting forms and to healthy controls. EGF plasma levels are inversely correlated with clinical disability, and low EGF plasma levels combined with other biomarkers (HGF, Eotaxin/CCL11, and MIP-1β/CCL4) predicts the form of progressive MS (Tejera-Alhambra et al., 2015). Blood EGF levels increase after improvement in MS patient’s nutritional and clinical status (Reginald McDaniel et al., 2020). Furthermore, HB-EGF expression is increased in reactive astrocytes of MS brain active lesions (Schenk et al., 2013). Together, these observations suggest that EGFR signaling may have a predominantly regenerative role in MS through its effects on oligodendrocyte biology and remyelination, although local activation of the pathway within inflammatory lesions may exert distinct effects that require further investigation. These findings distinguish MS from other neurodegenerative disorders discussed in this review, as the predominant therapeutic goal may be to enhance regenerative EGFR signaling rather than suppress receptor activity.

1.3.5 Huntington’s disease

EGFR’s role in Huntington’s disease (HD) is not well defined; in HD in vitro models, cells carrying mutant huntingtin have increased activation of AKT and MEK signaling activation downstream of the EGFR upon EGF stimulation. This may promote to aberrant huntingtin subcellular localization, altering gene expression (Bowles et al., 2015). In addition, in human HD fibroblasts, mutant huntingtin causes a delay in EGFR degradation and altered trafficking (Melone et al., 2013). Although these findings suggest that mutant huntingtin can influence EGFR signaling dynamics, evidence directly linking EGFR dysfunction to HD pathogenesis remains sparse. Consequently, no clear conclusions can currently be drawn regarding the therapeutic potential of targeting EGFR in HD. Whether this reflects a genuinely limited contribution of EGFR signaling to HD pathogenesis or simply an underexplored area of research remains unclear.

1.4 Targeting the EGFR pathway to treat neurodegenerative diseases

Given its dual roles, EGFR represents a challenging but promising therapeutic target. A major obstacle is that EGFR signaling can exert either beneficial or detrimental effects depending on the signaling intensity, ligand availability, receptor dimerization, and downstream pathway bias, the disease context, cell type, and stage of disease progression. Consequently, therapeutic approaches targeting EGFR signaling must consider the temporal and spatial context of pathway modulation, as well as the degree of EGFR activity alteration required to achieve beneficial effects. To date, no EGFR-targeted agents have entered neurological clinical trials. EGFR signaling has been explored mainly in preclinical models of brain injury and neuroinflammation. Furthermore, most available studies rely on acute injury models or transgenic animal models, and their translational relevance to human disease remains unclear.

Optimal dosing regimens are largely unexplored. Key controversies include whether EGFR should be stimulated (to harness its neurotrophic functions) or blocked (to reduce maladaptive gliosis), where evidence exists for both approaches (White et al., 2011; Romano and Bucci, 2020; Badenes, 2024). The available literature suggests that these apparently opposing strategies may not be mutually exclusive. Instead, they likely reflect distinct biological functions of EGFR signaling. Transient ligand-driven activation may support neurogenesis, remyelination, neuronal survival, and tissue repair, whereas chronic or dysregulated EGFR activation may contribute to neuroinflammation, reactive gliosis, and neurodegeneration. This framework raises the possibility that therapeutic benefit may depend on restoring physiological EGFR signaling rather than simply activating or inhibiting the pathway. Accordingly, future therapeutic approaches may need to selectively enhance regenerative EGFR signaling while simultaneously limiting pathological signaling in reactive glial or inflammatory cells. Patient heterogeneity will also be important. For example, EGFR inhibition may prove beneficial in disorders characterized by chronic neuroinflammation and pathological protein aggregation, whereas enhancing EGFR signaling may be more appropriate in conditions where regenerative capacity is impaired, such as demyelinating diseases. Identifying biomarkers that distinguish these disease states and define EGFR signaling status in individual patients will therefore be critical for patient stratification and treatment selection. Safety remains a major concern because EGFR is a proto-oncogene, and chronic pathway activation may increase the risk of tumorigenesis. Conversely, prolonged inhibition can impair endogenous repair mechanisms.

Directly administering EGFR ligands (EGF, TGF-α, HB-EGF) may hold therapeutic potential for neurodegenerative diseases, but may depend on co-administration of other growth factors (White et al., 2011; Hernández-Bernal et al., 2024; Sun et al., 2010; Türeyen et al., 2005). Accordingly, EGF combined with growth hormone-releasing hexapeptide in a phase I/II clinical trial for acute ischemic stroke was found safe and led to favorable neurological and functional evolution and higher survival rates, supporting a Phase III study (Hernández-Bernal et al., 2024). Although stroke is not a neurodegenerative disease, these findings provide proof-of-principle that therapeutic manipulation of EGFR signaling in the CNS is feasible. Major challenges include ligand stability, controlling the duration and magnitude of receptor activation, and minimizing oncogenic risk. Potential solutions include viral vectors, engineered peptides, nanoparticles, and cell-based delivery systems designed for localized ligand exposure. Such targeted delivery strategies may also reduce systemic toxicity by restricting EGFR activation to CNS injured or degenerating regions.

In neurodegeneration models, blocking EGFR with tyrosine kinase inhibitors (TKIs) has shown promise. Blood brain barrier (BBB) penetration and dosing/timing are critical issues. Osimertinib has the highest BBB penetration (Choi et al., 2023), while AZD3759, a CNS-penetrant EGFR inhibitor, has demonstrated brain bioavailability and clinical activity (Yang et al., 2016). Other TKIs exhibit limited and variable BBB penetration. Despite encouraging preclinical findings, evidence supporting the use of EGFR inhibitors in neurodegenerative disease remains limited, and no agent has yet demonstrated efficacy in clinical neurological settings. Furthermore, EGFR TKIs (e.g., erlotinib, gefitinib, afatinib) are associated with common toxicities such as rash, and diarrhea during chronic use in cancer patients. Rare but serious adverse effects include interstitial lung disease and, less commonly, renal complications (Li et al., 2024). These safety considerations are particularly relevant when considering use in neurological settings, where long-term tolerability is critical, and may necessitate exploration of lower-dose or intermittent dosing strategies. In addition, because many neurological disorders require prolonged treatment, balancing efficacy with chronic safety will be particularly important when repurposing oncology-derived EGFR inhibitors. EGFR-blocking antibodies do not cross the BBB readily, but can be delivered intrathecally in theory. Their large size and immunogenicity are hurdles. Antibodies could be engineered (e.g., bispecific for BBB transport) to improve CNS delivery.

An emerging alternative is the selective targeting of individual components of the EGFR signaling network rather than global inhibition or activation of the receptor itself. Targeting specific ligands offers selectivity with fewer side effects. Neutralizing antibodies and RNA-based strategies targeting AREG are under preclinical and clinical development for fibrotic diseases (Schramm et al., 2022; Son et al., 2023). By blocking AREG-driven profibrotic signaling while preserving other ligands such as EGF and HB-EGF, such strategies may offer more precise control of tissue repair and pathological scarring. Extension of this concept to neuroinflammatory conditions remains speculative but mechanistically plausible. Inhibition of ADAM10 or ADAM17 or blocking ADAM17 regulators iRhoms and iTAP/FRMD8 are also possible approaches that can be therapeutically explored to limit EGFR activation. Because these interventions influence ligand availability rather than receptor activity itself, they may offer greater flexibility in shaping EGFR signaling outputs. Similarly, selectively modulating specific downstream signaling pathways rather than EGFR itself may eventually provide a means of preserving regenerative signaling while minimizing pathological responses. Finally, combinatorial approaches that integrate EGFR modulation with anti-inflammatory, neuroprotective, or remyelinating therapies may prove more effective than targeting EGFR signaling alone. Future therapeutic strategies will likely require cell-type-specific and temporally controlled modulation of EGFR signaling to maximize regenerative benefits while minimizing pathological consequences. Overall, the evidence reviewed here suggests that the future of EGFR-based therapy is unlikely to rely on simple receptor activation or inhibition, but rather on precision modulation of the EGFR signaling network tailored to disease stage, cellular context, and the underlying pathological mechanisms.

2 Discussion

The available literature indicates that EGFR signaling may occupy a pivotal position linking neuronal injury responses, neuroinflammation, and neurodegeneration. A central theme emerging is that the biological consequences of EGFR activation are highly dependent on the timing, magnitude, duration, cellular localization of signaling, and downstream pathway bias. Rather than acting as a purely beneficial or detrimental pathway, EGFR appears to function as a context-dependent regulator of CNS homeostasis, repair, and degeneration. This context dependency may explain many of the seemingly contradictory findings reported across models of neural injury and neurodegenerative disease. Furthermore, heterodimerization of EGFR with ErbB2, ErbB3, and particularly ErbB4 can alter downstream signaling outputs. Among these receptors, ErbB4/Neuregulin1 has by far the strongest evidence in CNS disease. Dysregulation of this pathway is strongly linked to schizophrenia, and is increasingly implicated in AD, epilepsy, and other neurodegenerative disorders (Turner-Ivey et al., 2025; Ding et al., 2024). Collectively, these observations suggest that EGFR should be viewed as part of a broader ErbB signaling network rather than as an isolated receptor, and that interactions among ErbB family members may substantially influence disease-specific biological outcomes.

In neural injury and neurodegenerative diseases, transient EGFR activation promotes neuronal survival, neural stem/progenitor cell proliferation, synaptic plasticity, and tissue repair, whereas chronic or dysregulated activation drives persistent neuroinflammation, reactive gliosis, glial scar formation, and neuronal dysfunction and degeneration (Romano and Bucci, 2020; Badenes, 2024). We hypothesize that the transition from reparative to pathogenic EGFR signaling is governed by a series of interconnected switches, including signal duration, receptor trafficking dynamics, crosstalk with inflammatory, fibrotic and mechanotransductive pathways, and cell-type-specific signaling responses. We speculate that acute EGFR activation generates transient ERK signaling pulses together with temporally restricted PI3K/AKT activation that promote regenerative transcriptional programs and neuronal survival. However, prolonged ligand exposure or impaired receptor trafficking may sustain EGFR mediated ERK/MAPK, JAK/STAT3, and maladaptive PI3K/AKT/mTOR activity in astrocytes and microglia, driving reactive gliosis, chronic cytokine production, and metabolic reprogramming, and contributing to aberrant activation of cell-cycle-associated transcriptional programs (Crozet and Levayer, 2023; Schultz et al., 2023; Patani et al., 2023; Qu et al., 2012; Chu et al., 2021; Liu et al., 2006; Herrup, 2012). Concomitant epigenetic remodeling may stabilize EGFR-driven neuroinflammatory and reactive glial phenotypes long after the initiating stimulus has diminished (Scholz et al., 2024). In addition, injury-induced inflammatory and profibrotic mediators, including TNF-α, IL-1β, IL-6, and TGF-β, may converge with and potentiate EGFR signaling to amplify ERK/MAPK- and STAT3-dependent transcription, promoting cytokine production, extracellular matrix remodeling, and reactive gliosis. We speculate that persistent crosstalk among these pathways establishes a feed-forward network that reinforces chronic neuroinflammation and pathological tissue remodeling (Liu et al., 2006; Patani et al., 2023; Chu et al., 2021; Meng et al., 2016). Furthermore, injury-driven YAP/TAZ activation may potentiate EGFR signaling by increasing the expression of EGFR ligands, EGFR-associated transcriptional programs, and other growth-factor signaling molecules, thereby establishing a positive feedback loop linking extracellular matrix remodeling and mechanotransduction to regenerative and inflammatory responses (Luo et al., 2025; Zhang et al., 2009; Vigneswaran et al., 2021). In neurodegenerative disorders, chronic exposure to protein aggregates and tissue stress signals may co-opt EGFR-associated signaling networks, shifting EGFR-associated signaling networks toward a persistent STAT3-dependent reactive astrocyte state that contributes to synaptic dysfunction, neuronal loss, and disease progression (Liu et al., 2006; Patani et al., 2023). Although several aspects of this model remain speculative, it provides a mechanistic framework that reconciles the apparently opposing effects of EGFR activation reported across different experimental systems and disease contexts.

Consequently, future studies should move beyond viewing EGFR as a single therapeutic target and instead focus on defining how EGFR signaling operates within specific cellular populations and disease stages. Emerging technologies such as single-cell transcriptomics, spatial transcriptomics, lineage tracing, spatial proteomics, and better translational models, including conditional cell-specific genetic models, will be particularly valuable for addressing these questions. Another gap is long-term safety: most neural repair studies are short-term. Chronic EGFR modulation could have unanticipated effects. Nevertheless, modulating EGFR offers therapeutic promise: delivering EGFR agonists (for instance, by administering EGF-like ligands) can enhance neurogenesis and neuronal survival, whereas EGFR inhibitors (e.g., with small-molecule inhibitors) can dampen neurotoxic pathology in diseases like AD, PD and ALS. Recent preclinical studies in rodents and zebrafish have established proof-of-concept for both approaches. Which strategy is preferable likely depends on disease timing, and cell and disease types. The field now faces the challenge of translating these insights: designing ligand-specific or context-dependent EGFR-targeted therapies that tip the balance toward healing. From a translational perspective, the current evidence suggests that therapeutic modulation of EGFR should be guided by the predominant biological process rather than by disease diagnosis alone. Conditions characterized by impaired regeneration, loss of neural progenitors, or demyelination may benefit from transient and spatially restricted EGFR activation to enhance neuronal survival, oligodendrocyte lineage expansion, remyelination, and tissue repair. In contrast, disorders dominated by chronic neuroinflammation, reactive astrogliosis, pathological protein aggregation, or glial scar formation may be more amenable to selective EGFR inhibition, particularly during later stages of disease when persistent EGFR signaling becomes maladaptive. These strategies should not be regarded as mutually exclusive but rather as complementary approaches that target distinct phases of disease progression. We therefore propose a conceptual therapeutic framework in which the optimal intervention depends on the timing of treatment, the predominant responding cell populations, and the balance between regenerative and pathogenic EGFR signaling. Future therapeutic approaches will likely require biomarker-guided, cell-specific, and temporally controlled modulation of EGFR activity rather than sustained global activation or inhibition. Such precision approaches may ultimately enable preservation of the physiological functions of EGFR while selectively suppressing pathological signaling pathways that drive disease progression. Given the dual nature of EGFR, personalized approaches (targeting EGFR only in appropriate cell types/times) will likely be necessary.

Overall, the evidence reviewed here supports a broader view of EGFR, moving beyond its role as simply a therapeutic target to recognizing it as a dynamic signaling hub whose biological effects are dictated by cellular context, disease stage, and network interactions. Harnessing this complexity, rather than circumventing it, may provide new opportunities for developing effective EGFR-based therapies for neurological disorders.

In summary, EGFR and its ligands are central regulators of CNS cell fate and repair. Leveraging this pathway for neurodegenerative diseases holds promise but requires nuanced understanding of cell-specific signaling and rigorous control of treatment parameters.

References

• 1

  AbjeanL.Ben HaimL.Riquelme-PerezM.GipchteinP.DerboisC.PalomaresM. A.et al. (2023). Reactive astrocytes promote proteostasis in Huntington's disease through the Jak2-Stat3 pathway. Brain146, 149–166. doi: 10.1093/brain/awac068,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  Adly SadikN.Ahmed RashedL.Ahmed Abd-El MawlaM. (2021). Circulating miR-155 and Jak2/Stat3 axis in acute ischemic stroke patients and its relation to post-ischemic inflammation and associated ischemic stroke risk factors. Int. J. Gen. Med.14, 1469–1484. doi: 10.2147/IJGM.S295939,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  AdrainC.BadenesM. (2024). Can the Hb-Egf/Egfr pathway restore injured neurons?FEBS J.291, 2094–2097. doi: 10.1111/febs.17143,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  AgeevaT.RizvanovA.MukhamedshinaY. (2024). Nf-κB and Jak/Stat signaling pathways as crucial regulators of Neuroinflammation and astrocyte modulation in spinal cord injury. Cells13:581. doi: 10.3390/cells13070581,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  AguirreA.DupreeJ. L.ManginJ. M.GalloV. (2007). A functional role for Egfr signaling in myelination and remyelination. Nat. Neurosci.10, 990–1002. doi: 10.1038/nn1938,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 6

  AlruwailiR.Al-KuraishyH. M.Al-GareebA. I.AlbuhadilyA. K.AlexiouA.PapadakisM.et al. (2025). Targeting of the Pi3 K/Akt/Gsk3β pathway in Parkinson's disease: a therapeutic blueprint. Mol. Neurobiol.62, 15108–15131. doi: 10.1007/s12035-025-05113-y,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  Amini-KhoeiH.SaghaeiE.MobiniG. R.Sabzevary-GhahfarokhiM.AhmadiR.BagheriN.et al. (2019). Possible involvement of Pi3K/Akt/mtor signaling pathway in the protective effect of selegiline (deprenyl) against memory impairment following ischemia reperfusion in rat. Neuropeptides77:101942. doi: 10.1016/j.npep.2019.101942,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  AnH.DuanY.WuD.YipJ.ElmadhounO.WrightJ. C.et al. (2017). Phenothiazines enhance mild hypothermia-induced neuroprotection via Pi3K/Akt regulation in experimental stroke. Sci. Rep.7:7469. doi: 10.1038/s41598-017-06752-5,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  AnsarS.EdvinssonL. (2008). Subtype activation and interaction of protein kinase C and mitogen-activated protein kinase controlling receptor expression in cerebral arteries and microvessels after subarachnoid hemorrhage. Stroke39, 185–190. doi: 10.1161/STROKEAHA.107.487827,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  ApolloniS.D'ambrosiN. (2025). Biochemical dissection of Stat3 signaling in amyotrophic lateral sclerosis. Neural Regen. Res.20, 3229–3230. doi: 10.4103/NRR.NRR-D-24-00862,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  ApolloniS.ParisiC.PesaresiM. G.RossiS.CarrìM. T.CozzolinoM.et al. (2013). The Nadph oxidase pathway is dysregulated by the P2X7 receptor in the Sod1-G93A microglia model of amyotrophic lateral sclerosis. J. Immunol.190, 5187–5195. doi: 10.4049/jimmunol.1203262,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  ArnésM.RomeroN.Casas-TintóS.AcebesÁ.FerrúsA. (2020). Pi3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposit formation. Mol. Biol. Cell31, 244–260. doi: 10.1091/mbc.E19-05-0303,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  AyalaV.Granado-SerranoA. B.CacabelosD.NaudíA.IlievaE. V.BoadaJ.et al. (2011). Cell stress induces Tdp-43 pathological changes associated with Erk1/2 dysfunction: implications in Als. Acta Neuropathol.122, 259–270. doi: 10.1007/s00401-011-0850-y,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  BadenesM. (2024). Epidermal growth factor receptor pathway in central nervous system regenerative medicine: a narrative review. Regener. Med. Rep.1, 172–186. doi: 10.4103/REGENMED.REGENMED-D-24-00020

  • CrossRef
  • Google Scholar

• 15

  BartusK.BurnsideE. R.GalinoJ.JamesN. D.BennettD. L. H.BradburyE. J. (2019). ErbB receptor signaling directly controls oligodendrocyte progenitor cell transformation and spontaneous remyelination after spinal cord injury. Glia,67, 1036–1046. doi: 10.1002/glia.23586,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  BarrettJ. P.HenryR. J.VillapolS.StoicaB. A.KumarA.BurnsM. P.et al. (2017). Nox2 deficiency alters macrophage phenotype through an Il-10/Stat3 dependent mechanism: implications for traumatic brain injury. J. Neuroinflammation14:65. doi: 10.1186/s12974-017-0843-4,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 17

  BathK. G.LeeF. S. (2010). Neurotrophic factor control of adult Svz neurogenesis. Dev. Neurobiol.70, 339–349. doi: 10.1002/dneu.20781,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 18

  Ben HaimL.CeyzériatK.Carrillo-De SauvageM. A.AubryF.AureganG.GuillermierM.et al. (2015). The Jak/Stat3 pathway is a common inducer of astrocyte reactivity in Alzheimer's and Huntington's diseases. J. Neurosci.35, 2817–2829. doi: 10.1523/JNEUROSCI.3516-14.2015,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 19

  BerryM.AhmedZ.DouglasM. R.LoganA. (2011). Epidermal growth factor receptor antagonists and Cns axon regeneration: mechanisms and controversies. Brain Res. Bull.84, 289–299. doi: 10.1016/j.brainresbull.2010.08.004,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  BhatiaV.VikramV.ChandelA.RattanA. (2025). Interplay between Pi3k/Akt signaling and caspase pathway in Alzheimer disease: mechanism and therapeutic implications. Inflammopharmacology33, 1785–1802. doi: 10.1007/s10787-025-01715-z,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  BhingeA.NambooriS. C.ZhangX.VandongenA. M. J.StantonL. W. (2017). Genetic correction of Sod1 mutant ipscs reveals Erk and Jnk activated Ap1 as a driver of neurodegeneration in amyotrophic lateral sclerosis. Stem Cell Rep.8, 856–869. doi: 10.1016/j.stemcr.2017.02.019,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  BianY.ChenY.WangX.CuiG.UngC. O. L.LuJ. H.et al. (2021). Oxyphylla a ameliorates cognitive deficits and alleviates neuropathology via the Akt-Gsk3β and Nrf2-Keap1-ho-1 pathways in vitro and in vivo murine models of Alzheimer’s disease. J. Adv. Res.34, 1–12. doi: 10.1016/j.jare.2021.09.002,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  BieberA. J.SuwansrinonK.KerkvlietJ.ZhangW.PeaseL. R.RodriguezM. (2010). Allelic variation in the Tyk2 and Egf genes as potential genetic determinants of Cns repair. Proc. Natl. Acad. Sci. U. S. A.107, 792–797. doi: 10.1073/pnas.0906589107,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 24

  BirecreeE.WhetsellW. O.StoscheckC.KingL. E.NanneyL. B. (1988). Immunoreactive epidermal growth factor receptors in neuritic plaques from patients with Alzheimer's disease. J. Neuropathol. Exp. Neurol.47, 549–560. doi: 10.1097/00005072-198809000-00006,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  BirknerK.WasserB.LoosJ.PlotnikovA.SegerR.ZippF.et al. (2017). The role of Erk signaling in experimental autoimmune encephalomyelitis. Int. J. Mol. Sci.18:1990. doi: 10.3390/ijms18091990,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  BodaiL.MarshJ. L. (2012). A novel target for Huntington’s disease: Erk at the crossroads of signaling. The Erk signaling pathway is implicated in Huntington’s disease and its upregulation ameliorates pathology. BioEssays34, 142–148. doi: 10.1002/bies.201100116,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  BorborM.YinD.BrockmeierU.WangC.DoeckelM.Pillath-EilersM.et al. (2023). Neurotoxicity of ischemic astrocytes involves Stat3-mediated metabolic switching and depends on glycogen usage. Glia71, 1553–1569. doi: 10.1002/glia.24357,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  BowlesK. R.BrooksS. P.DunnettS. B.JonesL. (2015). Huntingtin subcellular localisation is regulated by kinase Signalling activity in the StHdhQ111 model of Hd. PLoS One10:e0144864. doi: 10.1371/journal.pone.0144864,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  BreretonC. F.SuttonC. E.LalorS. J.LavelleE. C.MillsK. H. (2009). Inhibition of Erk Mapk suppresses Il-23- and Il-1-driven Il-17 production and attenuates autoimmune disease. J. Immunol.183, 1715–1723. doi: 10.4049/jimmunol.0803851,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  CantarellaC.CayreM.MagalonK.DurbecP. (2008). Intranasal Hb-Egf administration favors adult Svz cell mobilization to demyelinated lesions in mouse corpus callosum. Dev. Neurobiol.68, 223–236. doi: 10.1002/dneu.20588,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  CaoQ.QianM.WangX. F.WangB.WuH. W.ZhuX. J.et al. (2011). Negative feedback regulation of Raf/Mek/Erk cascade after sublethal cerebral ischemia in the rat hippocampus. Neurochem. Res.36, 153–162. doi: 10.1007/s11064-010-0285-1,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  ChenD.ChenJ. J.YinQ.GuanJ. H.LiuY. H. (2009). Role of Erk1/2 and vascular cell proliferation in cerebral vasospasm after experimental subarachnoid hemorrhage. Acta Neurochir.151, 1127–1134. doi: 10.1007/s00701-009-0385-3,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  ChenY. J.HsuC. C.ShiaoY. J.WangH. T.LoY. L.LinA. M. Y. (2019). Anti-inflammatory effect of afatinib (an Egfr-Tki) on Ogd-induced neuroinflammation. Sci. Rep.9:2516. doi: 10.1038/s41598-019-38676-7,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  ChenS.LathropK. L.KuwajimaT.GrossJ. M. (2022). Retinal ganglion cell survival after severe optic nerve injury is modulated by crosstalk between Jak/Stat signaling and innate immune responses in the zebrafish retina. Development149:694. doi: 10.1242/dev.199694,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  ChenY.LiZ. (2021). Protective effects of Propofol on rats with cerebral ischemia-reperfusion injury via the Pi3K/Akt pathway. J. Mol. Neurosci.71, 810–820. doi: 10.1007/s12031-020-01703-8,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 36

  ChenG.LiJ.WangZ.LiuW. (2020). Ezetimibe protects against spinal cord injury by regulating autophagy and apoptosis through inactivation of Pi3K/Akt/mtor signaling. Am. J. Transl. Res.12, 2685–2694,

  • Pubmed Abstract
  • Google Scholar

• 37

  ChenA.LinZ.LanL.XieG.HuangJ.LinJ.et al. (2012). Electroacupuncture at the Quchi and Zusanli acupoints exerts neuroprotective role in cerebral ischemia-reperfusion injured rats via activation of the Pi3K/Akt pathway. Int. J. Mol. Med.30, 791–796. doi: 10.3892/ijmm.2012.1074,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  ChenZ. H.LuoX. C.YuC. R.HuangL. (2020). Matrix metalloprotease-mediated cleavage of neural glial-related cell adhesion molecules activates quiescent olfactory stem cells via Egfr. Mol. Cell. Neurosci.108:103552. doi: 10.1016/j.mcn.2020.103552,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  ChenM.ReedR. R.LaneA. P. (2017). Acute inflammation regulates neuroregeneration through the Nf-κB pathway in olfactory epithelium. Proc. Natl. Acad. Sci. U. S. A.114, 8089–8094. doi: 10.1073/pnas.1620664114,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40

  ChenB.ShiG.XuJ.ZhangX.ZhuY.LiL.et al. (2025). Il-23 promotes neuronal ferroptosis via Il-23R/Stat3 signaling after traumatic brain injury. Cell Commun. Signal23:317. doi: 10.1186/s12964-025-02319-4,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  ChenC.TianX.ZhangW.WangX.ZhaoL.MaY.et al. (2026). Lep knockdown improves functional recovery after spinal cord injury and potentially regulates microglial polarization via Jak-Stat signaling pathway. NeuroMolecular Med.28:8930. doi: 10.1007/s12017-026-08930-z,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  ChenT. J.WangD. C.ChenS. S. (2009). Amyloid-beta interrupts the Pi3K-Akt-mtor signaling pathway that could be involved in brain-derived neurotrophic factor-induced arc expression in rat cortical neurons. J. Neurosci. Res.87, 2297–2307. doi: 10.1002/jnr.22057,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  ChenL.WeiX.HouY.LiuX.LiS.SunB.et al. (2014). Tetramethylpyrazine analogue Cxc195 protects against cerebral ischemia/reperfusion-induced apoptosis through Pi3K/Akt/Gsk3β pathway in rats. Neurochem. Int.66, 27–32. doi: 10.1016/j.neuint.2014.01.006,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  ChibaT.YamadaM.AisoS. (2009a). Targeting the Jak2/Stat3 axis in Alzheimer’s disease. Expert Opin. Ther. Targets13, 1155–1167. doi: 10.1517/14728220903213426,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  ChibaT.YamadaM.SasabeJ.TerashitaK.ShimodaM.MatsuokaM.et al. (2009b). Amyloid-beta causes memory impairment by disturbing the Jak2/Stat3 axis in hippocampal neurons. Mol. Psychiatry14, 206–222. doi: 10.1038/mp.2008.105,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  ChoiH. J.JeongY. J.KimJ.HoeH. S. (2023). Egfr is a potential dual molecular target for cancer and Alzheimer's disease. Front. Pharmacol.14:1238639. doi: 10.3389/fphar.2023.1238639,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  ChoiJ. S.KimS. Y.ChaJ. H.ChoiY. S.SungK. W.OhS. T.et al. (2003a). Upregulation of gp130 and Stat3 activation in the rat hippocampus following transient forebrain ischemia. Glia41, 237–246. doi: 10.1002/glia.10186,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48

  ChoiJ. S.KimS. Y.ParkH. J.ChaJ. H.ChoiY. S.KangJ. E.et al. (2003b). Upregulation of gp130 and differential activation of Stat and p42/44 Mapk in the rat hippocampus following kainic acid-induced seizures. Brain Res. Mol. Brain Res.119, 10–18. doi: 10.1016/j.molbrainres.2003.08.010,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  ChuE.MychasiukR.HibbsM. L.SempleB. D. (2021). Dysregulated phosphoinositide 3-kinase signaling in microglia: shaping chronic neuroinflammation. J. Neuroinflammation18:276. doi: 10.1186/s12974-021-02325-6,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  ChungY. H.JooK. M.LimH. C.ChoM. H.KimD.LeeW. B.et al. (2005). Immunohistochemical study on the distribution of phosphorylated extracellular signal-regulated kinase (Erk) in the central nervous system of Sod1G93A transgenic mice. Brain Res.1050, 203–209. doi: 10.1016/j.brainres.2005.05.060,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  CieślakD.Szulc-KuberskaJ.StepieńH.KlimekA. (1986). Epidermal growth factor in human cerebrospinal fluid: reduced levels in amyotrophic lateral sclerosis. J. Neurol.233, 376–377. doi: 10.1007/BF00313927,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  CigliolaV.ShoffnerA.LeeN.OuJ.GonzalezT. J.HoqueJ.et al. (2023). Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer. Nat. Commun.14:4857. doi: 10.1038/s41467-023-40486-5,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  CohenS.CarpenterG.KingL. (1980). Epidermal growth factor-receptor-protein kinase interactions. Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity. J. Biol. Chem.255, 4834–4842. doi: 10.1016/S0021-9258(19)85573-4,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  ColinE.RégulierE.PerrinV.DürrA.BriceA.AebischerP.et al. (2005). Akt is altered in an animal model of Huntington's disease and in patients. Eur. J. Neurosci.21, 1478–1488. doi: 10.1111/j.1460-9568.2005.03985.x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  CrozetF.LevayerR. (2023). Emerging roles and mechanisms of Erk pathway mechanosensing. Cell. Mol. Life Sci.80:355. doi: 10.1007/s00018-023-05007-z,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 56

  Da RochaJ. F.BastosL.DominguesS. C.BentoA. R.KonietzkoU.Da CruzE.et al. (2021). App binds to the Egfr ligands Hb-Egf and Egf, acting synergistically with Egf to promote Erk signaling and Neuritogenesis. Mol. Neurobiol.58, 668–688. doi: 10.1007/s12035-020-02139-2,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  DangC.LuY.ChenX.LiQ. (2021). Baricitinib ameliorates experimental autoimmune encephalomyelitis by modulating the Janus kinase/signal transducer and activator of transcription signaling pathway. Front. Immunol.12:650708. doi: 10.3389/fimmu.2021.650708,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  Del BarcoD. G.MonteroE.Coro-AntichR. M.BrownE.Suarez-AlbaJ.LopezL.et al. (2011). Coadministration of epidermal growth factor and growth hormone releasing peptide-6 improves clinical recovery in experimental autoimmune encephalitis. Restor. Neurol. Neurosci.29, 243–252. doi: 10.3233/RNN-2011-0595,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  DienelA.VeettilR. A.MatsumuraK.ChoiH. A.Kumar TP.TsvetkovA. S.et al. (2021). Agonism of the α 7 _-acetylcholine receptor/Pi3K/Akt pathway promotes neuronal survival after subarachnoid hemorrhage in mice. Exp. Neurol.344:113792. doi: 10.1016/j.expneurol.2021.113792,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  DingY.ZhangY.ZhangL. (2024). The role of the neuregulin 1-ErbB4 signaling pathway in neurological disorders. J. Physiol. Pharmacol.75:1. doi: 10.26402/jpp.2024.6.01,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  DoetschF.PetreanuL.CailleI.Garcia-VerdugoJ. M.Alvarez-BuyllaA. (2002). Egf converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron36, 1021–1034. doi: 10.1016/S0896-6273(02)01133-9,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  DongC.WenS.ZhaoS.SunS.DongW.HanP.et al. (2021). Salidroside inhibits reactive Astrogliosis and glial scar formation in late cerebral ischemia via the Akt/Gsk-3β pathway. Neurochem. Res.46, 755–769. doi: 10.1007/s11064-020-03207-8,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  Dong-ChenX.YongC.YangX.Chen-YuS.Li-HuaP. (2023). Signaling pathways in Parkinson's disease: molecular mechanisms and therapeutic interventions. Signal Transduct. Target. Ther.8:73. doi: 10.1038/s41392-023-01353-3,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  DouglasM. R.MorrisonK. C.JacquesS. J.LeadbeaterW. E.GonzalezA. M.BerryM.et al. (2009). Off-target effects of epidermal growth factor receptor antagonists mediate retinal ganglion cell disinhibited axon growth. Brain132, 3102–3121. doi: 10.1093/brain/awp240,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  DuffyM. J.MulloolyM.O'donovanN.SukorS.CrownJ.PierceA.et al. (2011). The Adams family of proteases: new biomarkers and therapeutic targets for cancer?Clin. Proteomics8:9. doi: 10.1186/1559-0275-8-9,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  DzamkoN.ZhouJ.HuangY.HallidayG. M. (2014). Parkinson's disease-implicated kinases in the brain; insights into disease pathogenesis. Front. Mol. Neurosci.7:57. doi: 10.3389/fnmol.2014.00057,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  El-DessoukiA. M.ShalabyH. N.KhalafS. S.Abd-ElmawlaM. A.GhaiadH. R.Abdel MageedS. S.et al. (2026). Signaling pathways driving multiple sclerosis: from mechanisms to natural-product interventions. Biomed. Pharmacother.200:119543. doi: 10.1016/j.biopha.2026.119543,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  ElgindyA. M.El-AwadyE. E.El-SayedN. M.El-OrabiN. F.AtwaA. M. (2026). Neuroprotection by canagliflozin in a Huntington's disease model: role of Hif-1α and Pi3K/Akt signaling. Naunyn Schmiedeberg's Arch. Pharmacol.399, 8245–8262. doi: 10.1007/s00210-025-04891-5,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 69

  El-ShamarkaM. E.El-SaharA. E.SaadM. A.AssafN.SayedR. H. (2022). Inosine attenuates 3-nitropropionic acid-induced Huntington's disease-like symptoms in rats via the activation of the A2ar/Bdnf/Trkb/Erk/Creb signaling pathway. Life Sci.300:120569. doi: 10.1016/j.lfs.2022.120569,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  ErschbamerM.PernoldK.OlsonL. (2007). Inhibiting epidermal growth factor receptor improves structural, locomotor, sensory, and bladder recovery from experimental spinal cord injury. J. Neurosci.27, 6428–6435. doi: 10.1523/JNEUROSCI.1037-07.2007,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  FallonL.BélangerC. M.CoreraA. T.KontogianneaM.Regan-KlapiszE.MoreauF.et al. (2006). A regulated interaction with the Uim protein Eps15 implicates parkin in Egf receptor trafficking and pi(3)K-Akt signalling. Nat. Cell Biol.8, 834–842. doi: 10.1038/ncb1441,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  FaucherP.MonsN.MicheauJ.LouisC.BeracocheaD. J. (2015). Hippocampal injections of oligomeric amyloid β-peptide (1-42) induce selective working memory deficits and long-lasting alterations of Erk signaling pathway. Front. Aging Neurosci.7:245. doi: 10.3389/fnagi.2015.00245,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  FerrerI.AlcántaraS.BallabrigaJ.OlivéM.BlancoR.RiveraR.et al. (1996). Transforming growth factor-alpha (Tgf-alpha) and epidermal growth factor-receptor (Egf-R) immunoreactivity in normal and pathologic brain. Prog. Neurobiol.49, 99–119. doi: 10.1016/0301-0082(96)00009-3,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  FountaK.DafouD.KanataE.SklaviadisT.ZanosT. P.GounarisA.et al. (2023). Gene targeting in amyotrophic lateral sclerosis using causality-based feature selection and machine learning. Mol. Med.29:12. doi: 10.1186/s10020-023-00603-y,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  FujimotoM.ShibaM.KawakitaF.LiuL.NakasakiA.ShimojoN.et al. (2016). Epidermal growth factor-like repeats of tenascin-C-induced constriction of cerebral arteries via activation of epidermal growth factor receptors in rats. Brain Res.1642, 436–444. doi: 10.1016/j.brainres.2016.04.034,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  FujimotoM.ShibaM.KawakitaF.LiuL.ShimojoN.Imanaka-YoshidaK.et al. (2018). Effects of tenascin-C knockout on cerebral vasospasm after experimental subarachnoid hemorrhage in mice. Mol. Neurobiol.55, 1951–1958. doi: 10.1007/s12035-017-0466-x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  FujitaY.SatoA.YamashitaT. (2013). Brimonidine promotes axon growth after optic nerve injury through Erk phosphorylation. Cell Death Dis.4:e763. doi: 10.1038/cddis.2013.298,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  GabboujS.RyhänenS.MarttinenM.WittrahmR.TakaloM.KemppainenS.et al. (2019). Altered insulin signaling in Alzheimer's disease brain - special emphasis on Pi3K-Akt pathway. Front. Neurosci.13:629. doi: 10.3389/fnins.2019.00629,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  GanC. L.ZouY.ChenD.ShuiX.HuL.LiR.et al. (2022). Blocking Erk-Dapk1 Axis attenuates glutamate excitotoxicity in epilepsy. Int. J. Mol. Sci.23:126370. doi: 10.3390/ijms23126370,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  GautamV.RawatK.SandhuA.KumariP.SinghN.SahaL. (2021). An insight into crosstalk among multiple signaling pathways contributing to epileptogenesis. Eur. J. Pharmacol.910:174469. doi: 10.1016/j.ejphar.2021.174469,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  GetchellT. V.NarlaR. K.LittleS.HydeJ. F.GetchellM. L. (2000). Horizontal basal cell proliferation in the olfactory epithelium of transforming growth factor-alpha transgenic mice. Cell Tissue Res.299, 185–192. doi: 10.1007/s004419900149,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  GoldshmitY.GreenhalghC. J.TurnleyA. M. (2004a). Suppressor of cytokine signalling-2 and epidermal growth factor regulate neurite outgrowth of cortical neurons. Eur. J. Neurosci.20, 2260–2266. doi: 10.1111/j.1460-9568.2004.03698.x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  GoldshmitY.WaltersC. E.ScottH. J.GreenhalghC. J.TurnleyA. M. (2004b). Socs2 induces neurite outgrowth by regulation of epidermal growth factor receptor activation. J. Biol. Chem.279, 16349–16355. doi: 10.1074/jbc.M312873200,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  Gómez-OlivaR.Geribaldi-DoldánN.Domínguez-GarcíaS.Pardillo-DíazR.Martínez-OrtegaS.Oliva-MonteroJ. M.et al. (2023). Targeting epidermal growth factor receptor to recruit newly generated neuroblasts in cortical brain injuries. J. Transl. Med.21:867. doi: 10.1186/s12967-023-04707-1,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  Gómez-SantosC.FerrerI.ReirizJ.ViñalsF.BarrachinaM.AmbrosioS. (2002). Mpp+ increases alpha-synuclein expression and Erk/map-kinase phosphorylation in human neuroblastoma Sh-Sy5Y cells. Brain Res.935, 32–39. doi: 10.1016/S0006-8993(02)02422-8,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  Gómez-SuagaP.Rivero-RíosP.FdezE.Blanca RamírezM.FerrerI.AiastuiA.et al. (2014). Lrrk2 delays degradative receptor trafficking by impeding late endosomal budding through decreasing Rab7 activity. Hum. Mol. Genet.23, 6779–6796. doi: 10.1093/hmg/ddu395,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 87

  Gonzalez-PerezO.Romero-RodriguezR.Soriano-NavarroM.Garcia-VerdugoJ. M.Alvarez-BuyllaA. (2009). Epidermal growth factor induces the progeny of subventricular zone type B cells to migrate and differentiate into oligodendrocytes. Stem Cells27, 2032–2043. doi: 10.1002/stem.119,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  GotkineM.SchoenfeldD. A.CohenI.ShefnerJ. M.LernerY.CohenI. R.et al. (2025). Akt activation with Ipl344 treatment for amyotrophic lateral sclerosis: first in human, open-label study. Muscle Nerve71, 1032–1042. doi: 10.1002/mus.28393,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  GoyalA.AgrawalA.VermaA.DubeyN. (2023). The Pi3K-Akt pathway: a plausible therapeutic target in Parkinson's disease. Exp. Mol. Pathol.129:104846. doi: 10.1016/j.yexmp.2022.104846,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  GrabenstatterH. L.Del AngelY. C.CarlsenJ.WempeM. F.WhiteA. M.CogswellM.et al. (2014). The effect of Stat3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy. Neurobiol. Dis.62, 73–85. doi: 10.1016/j.nbd.2013.09.003,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  GudiV.ŠkuljecJ.YildizÖ.FrichertK.SkripuletzT.Moharregh-KhiabaniD.et al. (2011). Spatial and temporal profiles of growth factor expression during Cns demyelination reveal the dynamics of repair priming. PLoS One6:e22623. doi: 10.1371/journal.pone.0022623,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  HarderJ. M.BraineC. E.WilliamsP. A.ZhuX.MacnicollK. H.SousaG. L.et al. (2017). Early immune responses are independent of Rgc dysfunction in glaucoma with complement component C3 being protective. Proc. Natl. Acad. Sci. USA114, E3839–E3848. doi: 10.1073/pnas.1608769114,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  HashimotoY.SuzukiH.AisoS.NiikuraT.NishimotoI.MatsuokaM. (2005). Involvement of tyrosine kinases and Stat3 in Humanin-mediated neuroprotection. Life Sci.77, 3092–3104. doi: 10.1016/j.lfs.2005.03.031,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  Hernández-BernalF.Estenoz-GarcíaD.Gutiérrez-RonquilloJ. H.Martín-BautaY.Catasús-ÁlvarezK.Gutiérrez-CastilloM.et al. (2024). Combination therapy of epidermal growth factor and growth hormone-releasing Hexapeptide in acute ischemic stroke: a phase I/ii non-blinded, randomized clinical trial. Front. Neurol.15:1303402. doi: 10.3389/fneur.2024.1303402,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  HerrmannJ. E.ImuraT.SongB.QiJ.AoY.NguyenT. K.et al. (2008). Stat3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J. Neurosci.28, 7231–7243. doi: 10.1523/JNEUROSCI.1709-08.2008,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 96

  HerrupK. (2012). The contributions of unscheduled neuronal cell cycle events to the death of neurons in Alzheimer's disease. Front. Biosci. (Elite Ed.)4, 2101–2109. doi: 10.2741/527,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 97

  HongH.WangY.MenardM.BuckleyJ. A.ZhouL.Volpicelli-DaleyL.et al. (2024). Suppression of the Jak/Stat pathway inhibits neuroinflammation in the line 61-Pff mouse model of Parkinson's disease. J. Neuroinflammation21:216. doi: 10.1186/s12974-024-03210-8,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  HsiehL. S.WenJ. H.NguyenL. H.ZhangL.GetzS. A.Torres-ReveronJ.et al. (2020). Ectopic Hcn4 expression drives mtor-dependent epilepsy in mice. Sci. Transl. Med.12:1492. doi: 10.1126/scitranslmed.abc1492,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  HuangY. Y.LinS. J.ChiangW. Y.ChangY. T.YangC. C.LiaoC. Y.et al. (2025). Egfr phosphorylates Dnajb1 to suppress α-synuclein aggregation in Parkinson’s disease. NPJ Parkinsons Dis11:157. doi: 10.1038/s41531-025-01006-y,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  HuangN.ZhangY.ChenM.JinH.NieJ.LuoY.et al. (2019). Resveratrol delays 6-hydroxydopamine-induced apoptosis by activating the Pi3K/Akt signaling pathway. Exp. Gerontol.124:110653. doi: 10.1016/j.exger.2019.110653,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  HuangY. A.ZhouB.WernigM.SüdhofT. C. (2017). ApoE2, ApoE3, and ApoE4 differentially stimulate app transcription and aβ secretion. Cell168, 427–441.e21. doi: 10.1016/j.cell.2016.12.044,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  HumbertS.BrysonE. A.CordelièresF. P.ConnorsN. C.DattaS. R.FinkbeinerS.et al. (2002). The Igf-1/Akt pathway is neuroprotective in Huntington's disease and involves huntingtin phosphorylation by Akt. Dev. Cell2, 831–837. doi: 10.1016/S1534-5807(02)00188-0,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  HusainS.AhmadA.SinghS.PeterseimC.AbdulY.NutaitisM. J. (2017). Pi3K/Akt pathway: a role in δ-opioid receptor-mediated Rgc neuroprotection. Invest. Ophthalmol. Vis. Sci.58, 6489–6499. doi: 10.1167/iovs.16-20673,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  HusnjakK.DikicI. (2006). Egfr trafficking: Parkinson in a jam. Nat. Cell Biol.8, 787–788. doi: 10.1038/ncb0806-787,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 105

  IbiayoA. G.VarinthraP.NagarajanM.LiuI. Y. (2025). Coniferaldehyde reverses 3-nitropropionic acid-induced Huntington's disease pathologies via Pkm2 restoration and Jak2/Stat3 inhibition. Mol. Med.31:271. doi: 10.1186/s10020-025-01308-0,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  IwakuraY.NawaH. (2013). ErbB1-4-dependent Egf/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson's disease. Front. Cell. Neurosci.7:4. doi: 10.3389/fncel.2013.00004,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  IwakuraY.PiaoY. S.MizunoM.TakeiN.KakitaA.TakahashiH.et al. (2005). Influences of dopaminergic lesion on epidermal growth factor-ErbB signals in Parkinson’s disease and its model: neurotrophic implication in nigrostriatal neurons. J. Neurochem.93, 974–983. doi: 10.1111/j.1471-4159.2005.03073.x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 108

  JainM.SinghM. K.ShyamH.MishraA.KumarS.KumarA.et al. (2021). Role of Jak/Stat in the Neuroinflammation and its association with neurological disorders. Ann. Neurosci.28, 191–200. doi: 10.1177/09727531211070532,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  JayaswamyP. K.VijaykrishnarajM.PatilP.AlexanderL. M.KellaraiA.ShettyP. (2023). Implicative role of epidermal growth factor receptor and its associated signaling partners in the pathogenesis of Alzheimer’s disease. Ageing Res. Rev.83:101791. doi: 10.1016/j.arr.2022.101791,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  JiY.WangD.ZhangB.LuH. (2019). Bergenin ameliorates Mptp-induced Parkinson’s disease by activating Pi3K/Akt signaling pathway. J. Alzheimer's Dis72, 823–833. doi: 10.3233/JAD-190870,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  JiaC.HeggC. C. (2012). Neuropeptide Y and extracellular signal-regulated kinase mediate injury-induced neuroregeneration in mouse olfactory epithelium. Mol. Cell. Neurosci.49, 158–170. doi: 10.1016/j.mcn.2011.11.004,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  JimenezS.TorresM.VizueteM.Sanchez-VaroR.Sanchez-MejiasE.Trujillo-EstradaL.et al. (2011). Age-dependent accumulation of soluble amyloid beta (Abeta) oligomers reverses the neuroprotective effect of soluble amyloid precursor protein-alpha (sapp(alpha)) by modulating phosphatidylinositol 3-kinase (Pi3K)/Akt-Gsk-3beta pathway in Alzheimer mouse model. J. Biol. Chem.286, 18414–18425. doi: 10.1074/jbc.M110.209718,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  JuP.ZhangS.YeapY.FengZ. (2012). Induction of neuronal phenotypes from Ng2+ glial progenitors by inhibiting epidermal growth factor receptor in mouse spinal cord injury. Glia60, 1801–1814. doi: 10.1002/glia.22398,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 114

  JungS. Y.KimD. Y.YuneT. Y.ShinD. H.BaekS. B.KimC. J. (2014). Treadmill exercise reduces spinal cord injury-induced apoptosis by activating the Pi3K/Akt pathway in rats. Exp. Ther. Med.7, 587–593. doi: 10.3892/etm.2013.1451,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  JurcauA. (2022). Molecular pathophysiological mechanisms in Huntington’s disease. Biomedicine10:1432. doi: 10.3390/biomedicines10061432,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  KeshriP. K.SinghS. P. (2024). Unraveling the Akt/Erk cascade and its role in Parkinson disease. Arch. Toxicol.98, 3169–3190. doi: 10.1007/s00204-024-03829-9,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 117

  KhanM. R.YinX.KangS. U.MitraJ.WangH.RyuT.et al. (2023). Enhanced mtorc1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson's disease. Sci. Transl. Med.15:eadd0499. doi: 10.1126/scitranslmed.add0499,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 118

  KheyK. M. W.HuardA.MahmoudS. H. (2020). Inflammatory pathways following subarachnoid hemorrhage. Cell. Mol. Neurobiol.40, 675–693. doi: 10.1007/s10571-019-00767-4,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  KhezriM. R.YousefiK.EsmaeiliA.Ghasemnejad-BerenjiM. (2023). The role of Erk1/2 pathway in the pathophysiology of Alzheimer’s disease: An overview and update on new developments. Cell. Mol. Neurobiol.43, 177–191. doi: 10.1007/s10571-022-01191-x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  KirouacL.RajicA. J.CribbsD. H.PadmanabhanJ. (2017). Activation of Ras-Erk signaling and Gsk-3 by amyloid precursor protein and amyloid beta facilitates neurodegeneration in Alzheimer’s disease. eNeuro4:2017. doi: 10.1523/eneuro.0149-16.2017,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  KirschM.TrautmannN.ErnstM.HofmannH. D. (2010). Involvement of gp130-associated cytokine signaling in Müller cell activation following optic nerve lesion. Glia58, 768–779. doi: 10.1002/glia.20961,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  KitagishiY.NakanishiA.OguraY.MatsudaS. (2014). Dietary regulation of Pi3K/Akt/Gsk-3β pathway in Alzheimer’s disease. Alzheimer's Res. Ther.6:35. doi: 10.1186/alzrt265,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  KoprivicaV.ChoK. S.ParkJ. B.YiuG.AtwalJ.GoreB.et al. (2005). Egfr activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science310, 106–110. doi: 10.1126/science.1115462,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  KoriyamaY.HommaK.SugitaniK.HiguchiY.MatsukawaT.MurayamaD.et al. (2007). Upregulation of Igf-I in the goldfish retinal ganglion cells during the early stage of optic nerve regeneration. Neurochem. Int.50, 749–756. doi: 10.1016/j.neuint.2007.01.012,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  KornblumH. I.HussainR.WiesenJ.MiettinenP.ZurcherS. D.ChowK.et al. (1998). Abnormal astrocyte development and neuronal death in mice lacking the epidermal growth factor receptor. J. Neurosci. Res.53, 697–717. doi: 10.1002/(SICI)1097-4547(19980915)53:6<697::AID-JNR8>3.0.CO;2-0,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  KotelnikovaE.KianiN. A.MessinisD.PertsovskayaI.PliakaV.Bernardo-FauraM.et al. (2019). Mapk pathway and B cells overactivation in multiple sclerosis revealed by phosphoproteomics and genomic analysis. Proc. Natl. Acad. Sci. U. S. A.116, 9671–9676. doi: 10.1073/pnas.1818347116,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  KrzystekT. J.RathnayakeR.ZengJ.HuangJ.IacobucciG.YuM. C.et al. (2025). Opposing roles for Gsk3β and Erk1-dependent phosphorylation of huntingtin during neuronal dysfunction and cell death in Huntington's disease. Cell Death Dis.16:328. doi: 10.1038/s41419-025-07524-0,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  KuhnH. G.WinklerJ.KempermannG.ThalL. J.GageF. H. (1997). Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J. Neurosci.17, 5820–5829. doi: 10.1523/JNEUROSCI.17-15-05820.1997,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  KulichS. M.ChuC. T. (2001). Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: implications for Parkinson’s disease. J. Neurochem.77, 1058–1066. doi: 10.1046/j.1471-4159.2001.00304.x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  KumarS.MehanS.KhanZ.Das GuptaG.NarulaA. S. (2024). Guggulsterone selectively modulates Stat-3, mtor, and Ppar-gamma signaling in a methylmercury-exposed experimental neurotoxicity: evidence from Csf, blood plasma, and brain samples. Mol. Neurobiol.61, 5161–5193. doi: 10.1007/s12035-023-03902-x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  KumarS.PatelR.MooreS.CrawfordD. K.SuwannaN.MangiardiM.et al. (2013). Estrogen receptor β ligand therapy activates Pi3K/Akt/mtor signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis. Neurobiol. Dis.56, 131–144. doi: 10.1016/j.nbd.2013.04.005,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  Le PichonC. E.DominguezS. L.SolanoyH.NguH.Lewin-KohN.ChenM.et al. (2013). Egfr inhibitor erlotinib delays disease progression but does not extend survival in the Sod1 mouse model of Als. PLoS One8:e62342. doi: 10.1371/journal.pone.0062342,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  LeeJ.NguyenS.BhattacharyaS. (2024). Optic nerve regeneration: potential treatment approaches. Curr. Opin. Pharmacol.74:102428. doi: 10.1016/j.coph.2023.102428,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  LeiC.DengJ.WangB.ChengD.YangQ.DongH.et al. (2011). Reactive oxygen species scavenger inhibits Stat3 activation after transient focal cerebral ischemia-reperfusion injury in rats. Anesth. Analg.113, 153–159. doi: 10.1213/ANE.0b013e31821a9fbe,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  LiQ.ChengY.ZhangS.SunX.WuJ. (2021). Trpv4-induced Müller cell gliosis and Tnf-α elevation-mediated retinal ganglion cell apoptosis in glaucomatous rats via Jak2/Stat3/Nf-κB pathway. J. Neuroinflammation18:271. doi: 10.1186/s12974-021-02315-8,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  LiZ.ChuH.HuangS.LiR.QiuB.TanF.et al. (2024). Risk of treatment-related toxicity from EGFR tyrosine kinase inhibitors: a systematic review and network meta-analysis of randomized clinical trials in EGFR-mutant non-small cell lung cancer. J. Thorac. Dis.16, 6579–6594. doi: 10.21037/jtd-24-682,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 137

  LiJ.JiaZ.ZhangQ.DaiJ.KongJ.FanZ.et al. (2021). Inhibition of Erk1/2 phosphorylation attenuates spinal cord injury induced astrocyte activation and inflammation through negatively regulating aquaporin-4 in rats. Brain Res. Bull.170, 162–173. doi: 10.1016/j.brainresbull.2021.02.014,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  LiZ. W.LiJ. J.WangL.ZhangJ. P.WuJ. J.MaoX. Q.et al. (2014). Epidermal growth factor receptor inhibitor ameliorates excessive astrogliosis and improves the regeneration microenvironment and functional recovery in adult rats following spinal cord injury. J. Neuroinflammation11:71. doi: 10.1186/1742-2094-11-71,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 139

  LiH. C.ZhangG. Y. (2003). Inhibitory effect of genistein on activation of Stat3 induced by brain ischemia/reperfusion in rat hippocampus. Acta Pharmacol. Sin.24, 1131–1136,

  • Pubmed Abstract
  • Google Scholar

• 140

  LiZ. W.ZhaoJ. J.LiS. Y.CaoT. T.WangY.GuoY.et al. (2021). Blocking the Egfr/p38/Nf-κB signaling pathway alleviates disruption of Bscb and subsequent inflammation after spinal cord injury. Neurochem. Int.150:105190. doi: 10.1016/j.neuint.2021.105190,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  LiangZ.WuG.FanC.XuJ.JiangS.YanX.et al. (2016). The emerging role of signal transducer and activator of transcription 3 in cerebral ischemic and hemorrhagic stroke. Prog. Neurobiol.137, 1–16. doi: 10.1016/j.pneurobio.2015.11.001,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  LinF. X.GuH. Y.HeW. (2025). Mapk signaling pathway in spinal cord injury: mechanisms and therapeutic potential. Exp. Neurol.383:115043. doi: 10.1016/j.expneurol.2024.115043,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  LiuB.ChenH.JohnsT. G.NeufeldA. H. (2006). Epidermal growth factor receptor activation: an upstream signal for transition of quiescent astrocytes into reactive astrocytes after neural injury. J. Neurosci.26, 7532–7540. doi: 10.1523/JNEUROSCI.1004-06.2006,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  LiuY.HoldbrooksA. T.De SarnoP.RowseA. L.YanagisawaL. L.McfarlandB. C.et al. (2014). Therapeutic efficacy of suppressing the Jak/Stat pathway in multiple models of experimental autoimmune encephalomyelitis. J. Immunol.192, 59–72. doi: 10.4049/jimmunol.1301513,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  LiuT.LiX.ZhouX.ChenW.WenA.LiuM.et al. (2025). Pi3K/Akt signaling and neuroprotection in ischemic stroke: molecular mechanisms and therapeutic perspectives. Neural Regen. Res.20, 2758–2775. doi: 10.4103/NRR.NRR-D-24-00568,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 146

  LiuK.LuY.LeeJ. K.SamaraR.WillenbergR.Sears-KraxbergerI.et al. (2010). Pten deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci.13, 1075–1081. doi: 10.1038/nn.2603,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 147

  LiuB.NeufeldA. H. (2003). Activation of epidermal growth factor receptor signals induction of nitric oxide synthase-2 in human optic nerve head astrocytes in glaucomatous optic neuropathy. Neurobiol. Dis.13, 109–123. doi: 10.1016/S0969-9961(03)00010-X,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  LiuB.NeufeldA. H. (2004). Activation of epidermal growth factor receptors directs astrocytes to organize in a network surrounding axons in the developing rat optic nerve. Dev. Biol.273, 297–307. doi: 10.1016/j.ydbio.2004.06.006,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  LiuR.TangJ. C.PanM. X.ZhuangY.ZhangY.LiaoH. B.et al. (2018). Erk 1/2 activation mediates the neuroprotective effect of BpV(pic) in focal cerebral ischemia-reperfusion injury. Neurochem. Res.43, 1424–1438. doi: 10.1007/s11064-018-2558-z,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 150

  LiuS. M.XiaoZ. F.LiX.ZhaoY. N.WuX. M.HanJ.et al. (2019). Vascular endothelial growth factor activates neural stem cells through epidermal growth factor receptor signal after spinal cord injury. CNS Neurosci. Ther.25, 375–385. doi: 10.1111/cns.13056,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  LundI. V.HuY.RaolY. H.BenhamR. S.FarisR.RussekS. J.et al. (2008). Bdnf selectively regulates Gabaa receptor transcription by activation of the Jak/Stat pathway. Sci. Signal.1:ra9. doi: 10.1126/scisignal.1162396

  • CrossRef
  • Google Scholar

• 152

  LuoJ. X.WangD. M.RanZ.LuM. H. (2025). Yap/Taz in the nervous system: key regulatory and therapeutic implications in neurological disorders. Behav. Brain Res.493:115672. doi: 10.1016/j.bbr.2025.115672,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  LvX.LiangJ.WangZ. (2024). MiR-21-5p reduces apoptosis and inflammation in rats with spinal cord injury through Pi3K/Akt pathway. Panminerva Med.66, 256–265. doi: 10.23736/S0031-0808.20.03974-9,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  LvS.ZhaoK.LiR.MengC.LiG.YinF. (2024). Egfr-activated Jak2/Stat3 pathway confers neuroprotection in spinal cord ischemia-reperfusion injury: evidence from high-throughput sequencing and experimental models. Mol. Neurobiol.61, 646–661. doi: 10.1007/s12035-023-03548-9,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  MaddahiA.AnsarS.ChenQ.EdvinssonL. (2011). Blockade of the Mek/Erk pathway with a raf inhibitor prevents activation of pro-inflammatory mediators in cerebral arteries and reduction in cerebral blood flow after subarachnoid hemorrhage in a rat model. J. Cereb. Blood Flow Metab.31, 144–154. doi: 10.1038/jcbfm.2010.62,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  MaddahiA.PovlsenG. K.EdvinssonL. (2012). Regulation of enhanced cerebrovascular expression of proinflammatory mediators in experimental subarachnoid hemorrhage via the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway. J. Neuroinflammation9:274. doi: 10.1186/1742-2094-9-274,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  MagrìA.LipariC. L. R.RisiglioneP.ZimboneS.GuarinoF.CaccamoA.et al. (2023). Erk1/2-dependent Tspo overactivation associates with the loss of mitophagy and mitochondrial respiration in Als. Cell Death Dis.14:122. doi: 10.1038/s41419-023-05643-0,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  MaherP.DarguschR.BodaiL.GerardP. E.PurcellJ. M.MarshJ. L. (2011). Erk activation by the polyphenols fisetin and resveratrol provides neuroprotection in multiple models of Huntington's disease. Hum. Mol. Genet.20, 261–270. doi: 10.1093/hmg/ddq460,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  MammanaS.BramantiP.MazzonE.CavalliE.BasileM. S.FagoneP.et al. (2018). Preclinical evaluation of the Pi3K/Akt/mtor pathway in animal models of multiple sclerosis. Oncotarget9, 8263–8277. doi: 10.18632/oncotarget.23862,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  MansourH. M.FawzyH. M.El-KhatibA. S.KhattabM. M. (2022). Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer's disease. Neural Regen. Res.17, 1913–1918. doi: 10.4103/1673-5374.332132,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  MansourH. M.MohamedA. F.KhattabM. M.El-KhatibA. S. (2024). Unveiling the therapeutic prospects of Egfr inhibition in rotenone-mediated parkinsonism in rats: modulation of dopamine D3 receptor. Brain Res.1834:148893. doi: 10.1016/j.brainres.2024.148893,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  MeikleL.PollizziK.EgnorA.KramvisI.LaneH.SahinM.et al. (2008). Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mtor) inhibitors: effects on mtorc1 and Akt signaling lead to improved survival and function. J. Neurosci.28, 5422–5432. doi: 10.1523/JNEUROSCI.0955-08.2008,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  MeloneM. A.CalarcoA.PetilloO.MargarucciS.Colucci-D'amatoL.GalderisiU.et al. (2013). Mutant huntingtin regulates Egf receptor fate in non-neuronal cells lacking wild-type protein. Biochim. Biophys. Acta1832, 105–113. doi: 10.1016/j.bbadis.2012.09.001,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 164

  MengX. M.Nikolic-PatersonD. J.LanH. Y. (2016). Tgf-β: the master regulator of fibrosis. Nat. Rev. Nephrol.12, 325–338. doi: 10.1038/nrneph.2016.48,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  MichelK.ZhaoT.KarlM.LewisK.Fyffe-MaricichS. L. (2015). Translational control of myelin basic protein expression by Erk2 map kinase regulates timely remyelination in the adult brain. J. Neurosci.35, 7850–7865. doi: 10.1523/JNEUROSCI.4380-14.2015,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  MoriT.WangX.JungJ. C.SumiiT.SinghalA. B.FiniM. E.et al. (2002). Mitogen-activated protein kinase inhibition in traumatic brain injury: in vitro and in vivo effects. J. Cereb. Blood Flow Metab.22, 444–452. doi: 10.1097/00004647-200204000-00008,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167

  NakanoF.KanamaruH.KawakitaF.LiuL.NakatsukaY.NishikawaH.et al. (2023). Epidermal growth factor receptor mediates neuronal apoptosis after subarachnoid hemorrhage in mice. Stroke54, 1616–1626. doi: 10.1161/STROKEAHA.122.041977,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  NakanoF.KawakitaF.LiuL.NakatsukaY.NishikawaH.OkadaT.et al. (2019). Anti-vasospastic effects of epidermal growth factor receptor inhibitors after subarachnoid hemorrhage in mice. Mol. Neurobiol.56, 4730–4740. doi: 10.1007/s12035-018-1400-6,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  NaserpourL.JaliseS. Z.KhoshandamM.HosseinzadehF. (2025). Molecular mechanism and the main signaling pathways in the development and progression of multiple sclerosis. Exp. Cell Res.452:114769. doi: 10.1016/j.yexcr.2025.114769,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  NicolettiF.MazzonE.FagoneP.ManganoK.MammanaS.CavalliE.et al. (2019). Prevention of clinical and histological signs of Mog-induced experimental allergic encephalomyelitis by prolonged treatment with recombinant human Egf. J. Neuroimmunol.332, 224–232. doi: 10.1016/j.jneuroim.2019.05.006,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  NieX. G.FanD. S.HuangY. X.HeY. Y.DongB. L.GaoF. (2018). Downregulation of microrna-149 in retinal ganglion cells suppresses apoptosis through activation of the Pi3K/Akt signaling pathway in mice with glaucoma. Am. J. Physiol. Cell Physiol.315, C839–C849. doi: 10.1152/ajpcell.00324.2017,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  NinomiyaM.YamashitaT.ArakiN.OkanoH.SawamotoK. (2006). Enhanced neurogenesis in the ischemic striatum following Egf-induced expansion of transit-amplifying cells in the subventricular zone. Neurosci. Lett.403, 63–67. doi: 10.1016/j.neulet.2006.04.039,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  Nogueira-MachadoJ. A.Rocha-SilvaF.GomesN. A. (2025). The role of mtor in amyotrophic lateral sclerosis. Biomedicine13:952. doi: 10.3390/biomedicines13040952,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  OffenD.BarhumY.MelamedE.EmbacherN.SchindlerC.RansmayrG. (2009). Spinal cord mrna profile in patients with Als: comparison with transgenic mice expressing the human Sod-1 mutant. J. Mol. Neurosci.38, 85–93. doi: 10.1007/s12031-007-9004-z,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 175

  OhgomoriT.YamasakiR.TakeuchiH.KadomatsuK.KiraJ. I.JinnoS. (2017). Differential activation of neuronal and glial Stat3 in the spinal cord of the Sod1^G93A mouse model of amyotrophic lateral sclerosis. Eur. J. Neurosci.46, 2001–2014. doi: 10.1111/ejn.13650,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  OkazakiR.DoiT.HayakawaK.MoriokaK.ImamuraO.TakishimaK.et al. (2016). The crucial role of Erk2 in demyelinating inflammation in the central nervous system. J. Neuroinflammation13:235. doi: 10.1186/s12974-016-0690-8,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  OlivaA. A.KangY.Sanchez-MolanoJ.FuronesC.AtkinsC. M. (2012). Stat3 signaling after traumatic brain injury. J. Neurochem.120, 710–720. doi: 10.1111/j.1471-4159.2011.07610.x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  OsukaK.WatanabeY.UsudaN.AtsuzawaK.WakabayashiT.TakayasuM. (2010). Oxidative stress activates Stat1 in basilar arteries after subarachnoid hemorrhage. Brain Res.1332, 12–19. doi: 10.1016/j.brainres.2010.03.046,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  OsukaK.WatanabeY.YamauchiK.NakazawaA.UsudaN.TokudaM.et al. (2006). Activation of the Jak-Stat signaling pathway in the rat basilar artery after subarachnoid hemorrhage. Brain Res.1072, 1–7. doi: 10.1016/j.brainres.2005.12.003,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 180

  ÖzbeyliD.SariG.ÖzkanN.KarademirB.YükselM.Çilingir KayaÖ.et al. (2017). Protective effects of different exercise modalities in an Alzheimer's disease-like model. Behav. Brain Res.328, 159–177. doi: 10.1016/j.bbr.2017.03.044,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  PalanivelV.GuptaV.ChitranshiN.TietzO.Vander WallR.BladesR.et al. (2024). Neuropeptide Y receptor activation preserves inner retinal integrity through Pi3K/Akt signaling in a glaucoma mouse model. Pnas Nexus3:pgae299. doi: 10.1093/pnasnexus/pgae299,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  Pastor-AlonsoO.DuráI.Bernardo-CastroS.VareaE.Muro-GarcíaT.Martín-SuárezS.et al. (2024). Hb-Egf activates Egfr to induce reactive neural stem cells in the mouse hippocampus after seizures. Life Sci. Alliance7:e202201840. doi: 10.26508/lsa.202201840,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  PataniR.HardinghamG. E.LiddelowS. A. (2023). Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration. Nat. Rev. Neurol.19, 395–409. doi: 10.1038/s41582-023-00822-1,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  PengJ.ZuoY.HuangL.OkadaT.LiuS.ZuoG.et al. (2019). Activation of Gpr30 with G1 attenuates neuronal apoptosis via src/Egfr/stat3 signaling pathway after subarachnoid hemorrhage in male rats. Exp. Neurol.320:113008. doi: 10.1016/j.expneurol.2019.113008,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  PevianiM.CheroniC.TroglioF.QuartoM.PelicciG.BendottiC. (2007). Lack of changes in the Pi3K/Akt survival pathway in the spinal cord motor neurons of a mouse model of familial amyotrophic lateral sclerosis. Mol. Cell. Neurosci.34, 592–602. doi: 10.1016/j.mcn.2007.01.003,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  PrinaM. L.GoyetteA. R.AbdulkareemA. F.TariqK.BurgessN.SuJ.et al. (2026). Akt is necessary for neuronal hypertrophy and epilepsy caused by Pten knockout. Brain. doi: 10.1093/brain/awag098,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 187

  PrüßingK.VoigtA.SchulzJ. B. (2013). Drosophila melanogaster as a model organism for Alzheimer's disease. Mol. Neurodegener.8:35. doi: 10.1186/1750-1326-8-35,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  QiY.YangC.ZhaoH.DengZ.XuJ.LiangW.et al. (2022). Neuroprotective effect of sonic hedgehog mediated Pi3K/Akt pathway in amyotrophic lateral sclerosis model mice. Mol. Neurobiol.59, 6971–6982. doi: 10.1007/s12035-022-03013-z,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  QinT.LiC.XuY.QinY.JinY.HeR.et al. (2024). Local delivery of Egfr⁺Nscs-derived exosomes promotes neural regeneration post spinal cord injury via miR-34a-5p/Hdac6 pathway. Bioact. Mater.33, 424–443. doi: 10.1016/j.bioactmat.2023.11.013,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 190

  QuW. S.TianD. S.GuoZ. B.FangJ.ZhangQ.YuZ. Y.et al. (2012). Inhibition of Egfr/Mapk signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury. J. Neuroinflammation9:178. doi: 10.1186/1742-2094-9-178,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  RaibleD. J.FreyL. C.Brooks-KayalA. R. (2014). Effects of Jak2-Stat3 signaling after cerebral insults. Jakstat3:e29510. doi: 10.4161/jkst.29510,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  RavizzaT.ScheperM.Di SapiaR.GorterJ.AronicaE.VezzaniA. (2024). Mtor and neuroinflammation in epilepsy: implications for disease progression and treatment. Nat. Rev. Neurosci.25, 334–350. doi: 10.1038/s41583-024-00805-1,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  Reginald McdanielH.LagankeC.BloomL.GoldbergS.LagesL. C.LantiguaL. A.et al. (2020). The effect of a polysaccharide-based multinutrient dietary supplementation regimen on infections and immune functioning in multiple sclerosis. J. Diet Suppl.17, 184–199. doi: 10.1080/19390211.2018.1495675,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  RibeiroM.RosenstockT. R.OliveiraA. M.OliveiraC. R.RegoA. C. (2014). Insulin and Igf-1 improve mitochondrial function in a pi-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington's disease knock-in striatal cells. Free Radic. Biol. Med.74, 129–144. doi: 10.1016/j.freeradbiomed.2014.06.023,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  RichardsonP. J.SmithD. P.De GiorgioA.SnetkovX.Almond-ThynneJ.CroninS.et al. (2023). Janus kinase inhibitors are potential therapeutics for amyotrophic lateral sclerosis. Transl Neurodegener12:47. doi: 10.1186/s40035-023-00380-y,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  RomanoR.BucciC. (2020). Role of Egfr in the nervous system. Cells9:1887. doi: 10.3390/cells9081887,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  RosenbaumD.SaftigP. (2024). New insights into the function and pathophysiology of the ectodomain sheddase a Disintegrin and metalloproteinase 10 (Adam10). FEBS J.291, 2733–2766. doi: 10.1111/febs.16870,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  RosenkranzA. A.SlastnikovaT. A. (2020). Epidermal growth factor receptor: key to selective intracellular delivery. Biochemistry (Mosc)85, 967–993. doi: 10.1134/S0006297920090011,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  RusekM.SmithJ.El-KhatibK.AikinsK.CzuczwarS. J.PlutaR. (2023). The role of the Jak/Stat signaling pathway in the pathogenesis of Alzheimer’s disease: new potential treatment target. Int. J. Mol. Sci.24:864. doi: 10.3390/ijms24010864,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  RussoC.DolciniV.SalisS.VeneziaV.ZambranoN.RussoT.et al. (2002). Signal transduction through tyrosine-phosphorylated C-terminal fragments of amyloid precursor protein via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain. J. Biol. Chem.277, 35282–35288. doi: 10.1074/jbc.M110785200,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  SaadM. I.JenkinsB. J. (2024). The protease Adam17 at the crossroads of disease: revisiting its significance in inflammation, cancer, and beyond. FEBS J.291, 10–24. doi: 10.1111/febs.16923,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  SaavedraA.García-MartínezJ. M.XifróX.GiraltA.Torres-PerazaJ. F.CanalsJ. M.et al. (2010). Ph domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the Pi3K/Akt pro-survival pathway in Huntington's disease striatum. Cell Death Differ.17, 324–335. doi: 10.1038/cdd.2009.127,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  SahanaT. G.ZhangK. (2021). Mitogen-activated protein kinase pathway in amyotrophic lateral sclerosis. Biomedicine9:969. doi: 10.3390/biomedicines9080969,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 204

  SahuR.UpadhayayS.MehanS. (2021). Inhibition of extracellular regulated kinase (Erk)-1/2 signaling pathway in the prevention of Als: target inhibitors and influences on neurological dysfunctions. Eur. J. Cell Biol.100:151179. doi: 10.1016/j.ejcb.2021.151179,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205

  SalemM. A.RabieM. A.El MaraghyN. N.El-SaidY. A. M.El SayedN. S.MansourS. M. (2025). Unlocking dexmedetomidine's therapeutic potential in multiple sclerosis: dual modulation of Pi3K/Akt/Bdnf and Tlr4/Nf-κB pathways in Eae rats. Eur. J. Pharmacol.1008:178365. doi: 10.1016/j.ejphar.2025.178365,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  SalkarA.WallR. V.BasavarajappaD.ChitranshiN.ParillaG. E.MirzaeiM.et al. (2024). Glial cell activation and immune responses in Glaucoma: a systematic review of human postmortem studies of the retina and optic nerve. Aging Dis.15, 2069–2083. doi: 10.14336/AD.2024.0103,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  SamrajA. K.MüllerA. H.GrellA. S.EdvinssonL. (2014). Role of unphosphorylated transcription factor Stat3 in late cerebral ischemia after subarachnoid hemorrhage. J. Cereb. Blood Flow Metab.34, 759–763. doi: 10.1038/jcbfm.2014.15,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  SarantosM. R.PapanikolaouT.EllerbyL. M.HughesR. E. (2012). Pizotifen activates Erk and provides neuroprotection in vitro and in vivo in models of Huntington's disease. J. Huntingtons Dis.1, 195–210. doi: 10.3233/JHD-120033,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  SayedN. H.FathyN.KortamM. A.RabieM. A.MohamedA. F.KamelA. S. (2020). Vildagliptin attenuates Huntington's disease through activation of Glp-1 receptor/Pi3K/Akt/Bdnf pathway in 3-Nitropropionic acid rat model. Neurotherapeutics17, 252–268. doi: 10.1007/s13311-019-00805-5,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  ScalabrinoG.GalimbertiD.MuttiE.ScalabriniD.VeberD.De RizM.et al. (2010). Loss of epidermal growth factor regulation by cobalamin in multiple sclerosis. Brain Res.1333, 64–71. doi: 10.1016/j.brainres.2010.03.073,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  ScalabrinoG.VeberD.De GiuseppeR.RoncaroliF. (2015). Low levels of cobalamin, epidermal growth factor, and normal prions in multiple sclerosis spinal cord. Neuroscience298, 293–301. doi: 10.1016/j.neuroscience.2015.04.020,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  ScafidiJ.HammondT. R.ScafidiS.RitterJ.JablonskaB.RoncalM.et al. (2014). Intranasal epidermal growth factor treatment rescues neonatal brain injury. Nature,506, 230–234. doi: 10.1038/nature12880,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 213

  SchanbacherC.BieberM.ReindersY.CherpokovaD.TeichertC.NieswandtB.et al. (2022). Erk1/2 activity is critical for the outcome of ischemic stroke. Int. J. Mol. Sci.23:706. doi: 10.3390/ijms23020706,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214

  SchenkG. J.DijkstraS.Van Het HofA. J.Van Der PolS. M.DrexhageJ. A.Van Der ValkP.et al. (2013). Roles for Hb-Egf and Cd9 in multiple sclerosis. Glia61, 1890–1905. doi: 10.1002/glia.22565,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  ScholzR.BrösamleD.YuanX.BeyerM.NeherJ. J. (2024). Epigenetic control of microglial immune responses. Immunol. Rev.323, 209–226. doi: 10.1111/imr.13317,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  SchrammF.SchaeferL.WygreckaM. (2022). Egfr Signaling in Lung Fibrosis. Cells11:986. doi: 10.3390/cells11060986,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  SchuldN. J.HussongS. A.KapphahnR. J.LehmannU.RoehrichH.RagehA. A.et al. (2015). Immunoproteasome deficiency protects in the retina after optic nerve crush. PLoS One10:e0126768. doi: 10.1371/journal.pone.0126768,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 218

  SchultzD. F.BilladeauD. D.JoisS. D. (2023). Egfr trafficking: effect of dimerization, dynamics, and mutation. Front. Oncol.13:1258371. doi: 10.3389/fonc.2023.1258371,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  ShabanN.KamashevD.EmelianovaA.BuzdinA. (2023). Targeted inhibitors of Egfr: structure, biology, biomarkers, and clinical applications. Cells13:10047. doi: 10.3390/cells13010047,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 220

  ShalabiM. G.Al-KuraishyH. M.ShokrM. M.BatihaG. E. (2026). Molecular crosstalk between Mapk signaling and neuroprotective pathways in Parkinson's disease: from pathogenesis to therapeutic potential. Neuroscience610, 297–310. doi: 10.1016/j.neuroscience.2026.06.026,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  ShaoS.ChenC.ShiG.ZhouY.WeiY.WuL.et al. (2023). Jak inhibition ameliorated experimental autoimmune encephalomyelitis by blocking gm-Csf-driven inflammatory signature of monocytes. Acta Pharm. Sin. B13, 4185–4201. doi: 10.1016/j.apsb.2023.07.026,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 222

  ShibaM.FujimotoM.Imanaka-YoshidaK.YoshidaT.TakiW.SuzukiH. (2014). Tenascin-C causes neuronal apoptosis after subarachnoid hemorrhage in rats. Transl. Stroke Res.5, 238–247. doi: 10.1007/s12975-014-0333-2,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  ShibataN.YamamotoT.HiroiA.OmiY.KatoY.KobayashiM. (2010). Activation of Stat3 and inhibitory effects of pioglitazone on Stat3 activity in a mouse model of Sod1-mutated amyotrophic lateral sclerosis. Neuropathology30, 353–360. doi: 10.1111/j.1440-1789.2009.01078.x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  SibiliaM.SteinbachJ. P.StinglL.AguzziA.WagnerE. F. (1998). A strain-independent postnatal neurodegeneration in mice lacking the Egf receptor. EMBO J.17, 719–731. doi: 10.1093/emboj/17.3.719,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  SireciS.KocagözY.AlkirazA. S.GülerK.DokuzluogluZ.BalciogluE.et al. (2024). Hb-Egf promotes progenitor cell proliferation and sensory neuron regeneration in the zebrafish olfactory epithelium. FEBS J.291, 2098–2133. doi: 10.1111/febs.17033,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 226

  SmitR. D.GhoshB.CampionT. J.StingelR.LavellE.HooperR.et al. (2024). Stat3 protects dopaminergic neurons against degeneration in animal model of Parkinson's disease. Brain Res.1824:148691. doi: 10.1016/j.brainres.2023.148691,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 227

  SonS. S.HwangS.ParkJ. H.KoY.YunS. I.LeeJ. H.et al. (2023). Author correction: in vivo silencing of amphiregulin by a novel effective self-assembled-micelle inhibitory Rna ameliorates renal fibrosis via inhibition of Egfr signals. Sci. Rep.13:11745. doi: 10.1038/s41598-023-38689-3,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  SosanyaN. M.BragerD. H.WolfeS.NiereF.Raab-GrahamK. F. (2015). Rapamycin reveals an mtor-independent repression of Kv1.1 expression during epileptogenesis. Neurobiol. Dis.73, 96–105. doi: 10.1016/j.nbd.2014.09.011,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  SumadewiK. T.HarkitasariS.TjandraD. C. (2023). Biomolecular mechanisms of epileptic seizures and epilepsy: a review. Acta Epileptol5:28. doi: 10.1186/s42494-023-00137-0,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  SunD.BullockM. R.AltememiN.ZhouZ.HagoodS.RolfeA.et al. (2010). The effect of epidermal growth factor in the injured brain after trauma in rats. J. Neurotrauma27, 923–938. doi: 10.1089/neu.2009.1209,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 231

  SunD.MooreS.JakobsT. C. (2017). Optic nerve astrocyte reactivity protects function in experimental glaucoma and other nerve injuries. J. Exp. Med.214, 1411–1430. doi: 10.1084/jem.20160412,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 232

  SuzukiH.FujimotoM.KawakitaF.LiuL.NakatsukaY.NakanoF.et al. (2020). Tenascin-C in brain injuries and edema after subarachnoid hemorrhage: findings from basic and clinical studies. J. Neurosci. Res.98, 42–56. doi: 10.1002/jnr.24330,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  SzewczakL.MachcińskaM.KierasińskaM.Zawadzka-WięchU.Maruszewska-CheruiyotM.MajewskiP.et al. (2025). Expression of Stat- and T-cell-related genes in women with first-line treatment of relapsing-remitting multiple sclerosis. Scand. J. Immunol.101:e13424. doi: 10.1111/sji.13424,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  TangJ.GuoW. C.HuJ. F.YuL. (2019). Let-7 participates in the regulation of inflammatory response in spinal cord injury through Pi3K/Akt signaling pathway. Eur. Rev. Med. Pharmacol. Sci.23, 6767–6773. doi: 10.26355/eurrev_201908_18714,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  TangS.LaiN.XuL. (2024). Neuronal pyroptosis mediated by Stat3 in early brain injury after subarachnoid hemorrhage. Brain Res.1822:148666. doi: 10.1016/j.brainres.2023.148666,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 236

  TavassolyO.Del Cid PelliteroE.LarroquetteF.CaiE.ThomasR. A.SoubannierV.et al. (2021). Pharmacological inhibition of brain Egfr activation by a Bbb-penetrating inhibitor, Azd3759, attenuates α-synuclein pathology in a mouse model of α-Synuclein propagation. Neurotherapeutics18, 979–997. doi: 10.1007/s13311-021-01017-6,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 237

  TavassolyO.SatoT.TavassolyI. (2020). Inhibition of brain epidermal growth factor receptor activation: a novel target in neurodegenerative diseases and brain injuries. Mol. Pharmacol.98, 13–22. doi: 10.1124/mol.120.119909,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  Tejera-AlhambraM.CasrougeA.De AndrésC.SeyfferthA.Ramos-MedinaR.AlonsoB.et al. (2015). Plasma biomarkers discriminate clinical forms of multiple sclerosis. PLoS One10:e0128952. doi: 10.1371/journal.pone.0128952,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  Ten BoschG. J. A.BolkJ.HartB. A.LamanJ. D. (2021). Multiple sclerosis is linked to Mapk^erk overactivity in microglia. J Mol Med (Berl)99, 1033–1042. doi: 10.1007/s00109-021-02080-4,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  TeramotoT.QiuJ.PlumierJ. C.MoskowitzM. A. (2003). Egf amplifies the replacement of parvalbumin-expressing striatal interneurons after ischemia. J. Clin. Invest.111, 1125–1132. doi: 10.1172/JCI200317170,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 241

  TezelG.ChauhanB. C.LeblancR. P.WaxM. B. (2003). Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma. Invest. Ophthalmol. Vis. Sci.44, 3025–3033. doi: 10.1167/iovs.02-1136,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  ThomasR.ZuchowskaP.MorrisA. W.MarottoliF. M.SunnyS.DeatonR.et al. (2016). Epidermal growth factor prevents Apoe4 and amyloid-beta-induced cognitive and cerebrovascular deficits in female mice. Acta Neuropathol. Commun.4:111. doi: 10.1186/s40478-016-0387-3

  • CrossRef
  • Google Scholar

• 243

  TortaroloM.Re CecconiA. D.CamporealeL.MargottaC.NardoG.PasettoL.et al. (2024). Sunitinib-mediated inhibition of Stat3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of Als. Neurobiol. Dis.199:106576. doi: 10.1016/j.nbd.2024.106576,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  TüreyenK.VemugantiR.BowenK. K.SailorK. A.DempseyR. J. (2005). EGF and FGF-2 infusion increases post-ischemic neural progenitor cell proliferation in the adult rat brain. Neurosurgery57, 1254–1263. doi: 10.1227/01.neu.0000186040.96929.8a,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 245

  Turner-IveyB.JenkinsD. P.CarrollS. L. (2025). Multiple roles for Neuregulins and their v-Erb-B2 avian Erythroblastic leukemia viral oncogene homolog receptors in neurodegenerative disease pathogenesis and therapy. Am. J. Pathol.195, 2015–2031. doi: 10.1016/j.ajpath.2025.03.012,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 246

  VenanziA. W.McgeeL. D.HackamA. S. (2025). Evaluating the evidence for neuroprotective and axonal regenerative activities of different inflammatory cell types after optic nerve injury. Mol. Neurobiol.62, 6212–6227. doi: 10.1007/s12035-024-04679-3,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 247

  VigneswaranK.BoydN. H.OhS. Y.LallaniS.BoucherA.NeillS. G.et al. (2021). Yap/Taz transcriptional coactivators create therapeutic vulnerability to Verteporfin in Egfr-mutant glioblastoma. Clin. Cancer Res.27, 1553–1569. doi: 10.1158/1078-0432.CCR-20-0018,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 248

  VikmanP.AnsarS.EdvinssonL. (2007). Transcriptional regulation of inflammatory and extracellular matrix-regulating genes in cerebral arteries following experimental subarachnoid hemorrhage in rats. Laboratory investigation. J. Neurosurg.107, 1015–1022. doi: 10.3171/JNS-07/11/1015,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 249

  WalkerC. L.LiuN. K.XuX. M. (2013). Pten/Pi3K and Mapk signaling in protection and pathology following Cns injuries. Front. Biol.8, 421–433. doi: 10.1007/s11515-013-1255-1,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 250

  WangZ.ChenX.ZhouL.WuD.CheX.YangG. (2003). Effects of extracellular signal-regulated kinase (Erk) on focal cerebral ischemia. Chin. Med. J.116, 1497–1503,

  • Pubmed Abstract
  • Google Scholar

• 251

  WangL.ChiangH. C.WuW.LiangB.XieZ.YaoX.et al. (2012). Epidermal growth factor receptor is a preferred target for treating amyloid-β-induced memory loss. Proc. Natl. Acad. Sci. USA109, 16743–16748. doi: 10.1073/pnas.1208011109,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 252

  WangL.LiangB.ZhongY. (2013). Reduced Egfr level potentially mediates the Aβ42-induced neuronal loss in transgenic fruit fly and mouse. Protein Cell4, 647–649. doi: 10.1007/s13238-013-3043-8,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 253

  WangC.OuyangS.ZhuX.JiangY.LuZ.GongP. (2023). Myricetin suppresses traumatic brain injury-induced inflammatory response via Egfr/Akt/Stat pathway. Sci. Rep.13:22764. doi: 10.1038/s41598-023-50144-x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 254

  WangX.SunL.HanX.LiZ.XingY.ChenX.et al. (2025a). The molecular mechanisms underlying retinal ganglion cell apoptosis and optic nerve regeneration in glaucoma (review). Int. J. Mol. Med.55:5504. doi: 10.3892/ijmm.2025.5504,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 255

  WangX.WangQ.HouL.WeiG.HeC.LiH.et al. (2025b). Advances in Erk signaling pathway in traumatic brain injury: mechanisms and therapeutic potential. Neurochem. Res.50:191. doi: 10.1007/s11064-025-04449-0,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 256

  WangB.WangX.YangS.LiuX.FengD.LuF.et al. (2016). Neuroprotective effects of nitidine in Parkinson's disease models through inhibiting microglia activation: role of the Jak2–Stat3 pathway. RSC Adv.6, 71328–71337. doi: 10.1039/c6ra11759g

  • CrossRef
  • Google Scholar

• 257

  WannerI. B.AndersonM. A.SongB.LevineJ.FernandezA.Gray-ThompsonZ.et al. (2013). Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via Stat3-dependent mechanisms after spinal cord injury. J. Neurosci.33, 12870–12886. doi: 10.1523/JNEUROSCI.2121-13.2013,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 258

  WeiZ.LiuJ.XieH.WangB.WuJ.ZhuZ. (2021). MiR-122-5p mitigates inflammation, reactive oxygen species and Sh-Sy5Y apoptosis by targeting Cpeb1 after spinal cord injury via the Pi3K/Akt signaling pathway. Neurochem. Res.46, 992–1005. doi: 10.1007/s11064-021-03232-1,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 259

  WenX.HuJ. (2024). Targeting Stat3 signaling pathway in the treatment of Alzheimer's disease with compounds from natural products. Int. Immunopharmacol.141:112936. doi: 10.1016/j.intimp.2024.112936,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 260

  WenY. T.ZhangJ. R.KapuparaK.TsaiR. K. (2019). mtorc2 activation protects retinal ganglion cells via Akt signaling after autophagy induction in traumatic optic nerve injury. Exp. Mol. Med.51, 1–11. doi: 10.1038/s12276-019-0298-z,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 261

  WhiteR. E.RaoM.GenselJ. C.MctigueD. M.KasparB. K.JakemanL. B. (2011). Transforming growth factor α transforms astrocytes to a growth-supportive phenotype after spinal cord injury. J. Neurosci.31, 15173–15187. doi: 10.1523/JNEUROSCI.3441-11.2011,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 262

  WuN.ZhaoY.XiaoM.LiuH.ChenH.LiuB.et al. (2025). Methylprednisolone modulates the Tfr/Tfh ratio in Eae-induced Neuroinflammation through the Pi3K/Akt/FoxO1 and Pi3K/Akt/mtor Signalling pathways. Inflammation48, 950–962. doi: 10.1007/s10753-024-02099-y,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 263

  XiaQ.HuQ.WangH.YangH.GaoF.RenH.et al. (2015). Induction of Cox-2-Pge2 synthesis by activation of the Mapk/Erk pathway contributes to neuronal death triggered by Tdp-43-depleted microglia. Cell Death Dis.6:e1702. doi: 10.1038/cddis.2015.69,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 264

  XiaoC. L.YinW. C.ZhongY. C.LuoJ. Q.LiuL. L.LiuW. Y.et al. (2022). The role of Pi3K/Akt signalling pathway in spinal cord injury. Biomed. Pharmacother.156:113881. doi: 10.1016/j.biopha.2022.113881,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 265

  XuZ.WangB. R.WangX.KuangF.DuanX. L.JiaoX. Y.et al. (2006). Erk1/2 and p38 mitogen-activated protein kinase mediate inos-induced spinal neuron degeneration after acute traumatic spinal cord injury. Life Sci.79, 1895–1905. doi: 10.1016/j.lfs.2006.06.023,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 266

  XuZ.XueT.ZhangZ.WangX.XuP.ZhangJ.et al. (2011). Role of signal transducer and activator of transcription-3 in up-regulation of Gfap after epilepsy. Neurochem. Res.36, 2208–2215. doi: 10.1007/s11064-011-0576-1,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 267

  XueW.ZhaoY.XiaoZ.WuX.MaD.HanJ.et al. (2020). Epidermal growth factor receptor-extracellular-regulated kinase blockade upregulates Trim32 signaling cascade and promotes neurogenesis after spinal cord injury. Stem Cells38, 118–133. doi: 10.1002/stem.3097,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 268

  YamauchiK.OsukaK.TakayasuM.UsudaN.NakazawaA.NakaharaN.et al. (2006). Activation of Jak/Stat signalling in neurons following spinal cord injury in mice. J. Neurochem.96, 1060–1070. doi: 10.1111/j.1471-4159.2005.03559.x,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 269

  YanX. B.HouH. L.WuL. M.LiuJ.ZhouJ. N. (2007). Lithium regulates hippocampal neurogenesis by Erk pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia. Neuropharmacology53, 487–495. doi: 10.1016/j.neuropharm.2007.06.020,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 270

  YangZ.GuoQ.WangY.ChenK.ZhangL.ChengZ.et al. (2016). Azd3759, a Bbb-penetrating Egfr inhibitor for the treatment of Egfr mutant Nsclc with Cns metastases. Sci. Transl. Med.8:368ra172. doi: 10.1126/scitranslmed.aag0976,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 271

  YangH.HongY.GongM.CaiS.YuanZ.FengS.et al. (2024). Fisetin exerts neuroprotective effects and oxidative stress after traumatic brain injury. Front. Pharmacol.15:1480345. doi: 10.3389/fphar.2024.1480345,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 272

  YangX.LuoC.CaiJ.PowellD. W.YuD.KuehnM. H.et al. (2011). Neurodegenerative and inflammatory pathway components linked to Tnf-α/Tnfr1 signaling in the glaucomatous human retina. Invest. Ophthalmol. Vis. Sci.52, 8442–8454. doi: 10.1167/iovs.11-8152,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 273

  YangL.WangH.LiuL.XieA. (2018). The role of insulin/Igf-1/Pi3K/Akt/Gsk3β signaling in Parkinson's disease dementia. Front. Neurosci.12:73. doi: 10.3389/fnins.2018.00073,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 274

  YinX.ChangJ.YangL.JiaL.HanJ.ChenL.et al. (2026). The Erk signaling pathway in cerebral ischemic stroke: mechanism and therapeutic significance. Biomed. Pharmacother.196:119058. doi: 10.1016/j.biopha.2026.119058,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 275

  YounD. H.JungH.LeeJ. H.PakS.HanS. W.KimJ. T.et al. (2026). Potential protective effects of naloxone in traumatic brain injury through Jak2/Stat3 signaling modulation. Life16:480. doi: 10.3390/life16030480,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 276

  YuL.ChenC.WangL. F.KuangX.LiuK.ZhangH.et al. (2013). Neuroprotective effect of kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of Nf-κB and Stat3 in transient focal stroke. PLoS One8:e55839. doi: 10.1371/journal.pone.0055839,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 277

  YuZ.DingR.YanQ.ChengM.LiT.ZhengF.et al. (2024). A novel network pharmacology strategy based on the universal effectiveness-common mechanism of medical herbs uncovers therapeutic targets in traumatic brain injury. Drug Des. Devel. Ther.18, 1175–1188. doi: 10.2147/DDDT.S450895,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 278

  YuC. G.YezierskiR. P. (2005). Activation of the Erk1/2 signaling cascade by excitotoxic spinal cord injury. Brain Res. Mol. Brain Res.138, 244–255. doi: 10.1016/j.molbrainres.2005.04.013,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 279

  YueW.DengX.WangZ.JiangM.HuR.DuanY.et al. (2023). Inhibition of the Mek/Erk pathway suppresses immune overactivation and mitigates Tdp-43 toxicity in a Drosophila model of Als. Immun. Ageing20:27. doi: 10.1186/s12979-023-00354-8,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 280

  YusufI. O.ChenH. M.ChengP. H.ChangC. Y.TsaiS. J.ChuangJ. I.et al. (2021). Fgf9 induces neurite outgrowth upon Erk signaling in knock-in striatal Huntington's disease cells. Life Sci.267:118952. doi: 10.1016/j.lfs.2020.118952,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 281

  ZhangJ.GuY.SunW.YuL.LiT. (2024). Tetrahydrocurcumin protects against Gsk3β/Pten/Pi3K/Akt-mediated Neuroinflammatory responses and microglial polarization following traumatic brain injury. Mol. Neurobiol.61, 7026–7036. doi: 10.1007/s12035-024-04034-6,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 282

  ZhangJ.JiJ. Y.YuM.OverholtzerM.SmolenG. A.WangR.et al. (2009). Yap-dependent induction of amphiregulin identifies a non-cell-autonomous component of the hippo pathway. Nat. Cell Biol.11, 1444–1450. doi: 10.1038/ncb1993,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 283

  ZhangC.JiangF.LiuS.NiH.FengZ.HuangM.et al. (2024). Trem1 promotes neuroinflammation after traumatic brain injury in rats: possible involvement of Erk/cpla2 signalling pathway. Neuroscience561, 74–86. doi: 10.1016/j.neuroscience.2024.09.036,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 284

  ZhangS.JuP.TjandraE.YeapY.OwlanjH.FengZ. (2016). Inhibition of epidermal growth factor receptor improves myelination and attenuates tissue damage of spinal cord injury. Cell. Mol. Neurobiol.36, 1169–1178. doi: 10.1007/s10571-015-0313-4,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 285

  ZhangH.XingZ.ZhengJ.ShiJ.CuiC. (2023). Ursolic acid ameliorates traumatic brain injury in mice by regulating microrna-141-mediated Pdcd4/Pi3K/Akt signaling pathway. Int. Immunopharmacol.120:110258. doi: 10.1016/j.intimp.2023.110258,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 286

  ZhangJ.XuX.ZhouD.LiH.YouW.WangZ.et al. (2015). Possible role of Raf-1 kinase in the development of cerebral vasospasm and early brain injury after experimental subarachnoid hemorrhage in rats. Mol. Neurobiol.52, 1527–1539. doi: 10.1007/s12035-014-8939-7,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 287

  ZhangP.ZhangL.ZhuL.ChenF.ZhouS.TianT.et al. (2015). The change tendency of Pi3K/Akt pathway after spinal cord injury. Am. J. Transl. Res.7, 2223–2232,

  • Pubmed Abstract
  • Google Scholar

• 288

  ZhaoX.LiZ.LiangS.LiS.RenJ.LiB.et al. (2019). Different epidermal growth factor receptor signaling pathways in neurons and astrocytes activated by extracellular matrix after spinal cord injury. Neurochem. Int.129:104500. doi: 10.1016/j.neuint.2019.104500,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 289

  ZhaoJ.LiG.ZhangY.SuX.HangC. (2011). The potential role of Jak2/Stat3 pathway on the anti-apoptotic effect of recombinant human erythropoietin (rhepo) after experimental traumatic brain injury of rats. Cytokine56, 343–350. doi: 10.1016/j.cyto.2011.07.018,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 290

  ZhengZ. V.ChenJ.LyuH.LamS. Y. E.LuG.ChanW. Y.et al. (2022). Novel role of Stat3 in microglia-dependent neuroinflammation after experimental subarachnoid haemorrhage. Stroke Vasc. Neurol.7, 62–70. doi: 10.1136/svn-2021-001028,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 291

  ZhengC.LiW.AliT.PengZ.LiuJ.PanZ.et al. (2023). Ibrutinib delays Als installation and increases survival of Sod1^G93A mice by modulating Pi3K/mtor/Akt signaling. J. Neuroimmune Pharmacol.18, 383–396. doi: 10.1007/s11481-023-10068-9,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 292

  ZhengB.YeL.ZhouY.ZhuS.WangQ.ShiH.et al. (2016). Epidermal growth factor attenuates blood-spinal cord barrier disruption via Pi3K/Akt/Rac1 pathway after acute spinal cord injury. J. Cell. Mol. Med.20, 1062–1075. doi: 10.1111/jcmm.12761,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 293

  ZhengY.ZengL.DongX.DuQ.GaoY. (2022). Periostin aggravates the early phase of traumatic brain injury via the Mapk/Erk pathway. Neurol. Res.44, 560–569. doi: 10.1080/01616412.2021.2024728,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 294

  ZhuQ.EnkhjargalB.HuangL.ZhangT.SunC.XieZ.et al. (2018). Aggf1 attenuates neuroinflammation and Bbb disruption via Pi3K/Akt/Nf-κB pathway after subarachnoid hemorrhage in rats. J. Neuroinflammation15:178. doi: 10.1186/s12974-018-1211-8,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 295

  ZhuL.HuangS.ChenW.LiK.ShengJ. (2026). Cytokines and related signaling pathways in traumatic brain injury. Front. Immunol.17:1738589. doi: 10.3389/fimmu.2026.1738589,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 296

  ZhuJ. H.KulichS. M.OuryT. D.ChuC. T. (2002). Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. Am. J. Pathol.161, 2087–2098. doi: 10.1016/S0002-9440(10)64487-2,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 297

  ZhuG.WangX.WuS.LiQ. (2012). Involvement of activation of Pi3K/Akt pathway in the protective effects of puerarin against Mpp+−induced human neuroblastoma Sh-Sy5Y cell death. Neurochem. Int.60, 400–408. doi: 10.1016/j.neuint.2012.01.003,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 298

  ZhuangZ.ZhaoX.WuY.HuangR.ZhuL.ZhangY.et al. (2011). The anti-apoptotic effect of Pi3K-Akt signaling pathway after subarachnoid hemorrhage in rats. Ann. Clin. Lab. Sci.41, 364–372,

  • Pubmed Abstract
  • Google Scholar

• 299

  ZongF.YouJ.WuH.WangX. (2025). Glial-mediated immune modulation in glaucomatous neurodegeneration: mechanisms and therapeutic implications. Front. Immunol.16:1640110. doi: 10.3389/fimmu.2025.1640110,

  • Pubmed Abstract
  • CrossRef
  • Google Scholar