Iron, an essential trace element, primarily participates in metabolic processes in the forms of Fe²⁺ and Fe³⁺ (Lee and Roh, 2025). Under physiological conditions, Fe²⁺ absorbed in the intestines or released from erythrocyte degradation is oxidized to Fe³⁺ by ceruloplasmin (CP) in the circulation. Fe³⁺ subsequently binds to transferrin (TF) or lactoferrin (LF) to form a TF–Fe³⁺ complex, which is then recognized and internalized by transferrin receptor 1 (TFR1) on the cell surface (Zhao et al., 2025b). Once inside the cell, Fe³⁺ is reduced to Fe²⁺ via six-transmembrane epithelial antigen of prostate 3 (STEAP3) and transported into the cytosol by divalent metal transporter 1 (DMT1) and ZRT/IRT-like proteins 8 and 14 (ZIP8/14) (Wang et al., 2025d). When iron stores are sufficient, most intracellular Fe²⁺ is sequestered in ferritin in an inactive form, while a small fraction forms the labile iron pool (LIP). Excess Fe²⁺ is exported via ferroportin (FPN) to maintain intracellular iron homeostasis (Wang et al., 2025d; Wang et al., 2025c). However, under conditions of iron overload, excess Fe²⁺ in the LIP undergoes Fenton chemistry with H₂O₂, producing excessive ROS, promoting lipid peroxidation, and ultimately triggering ferroptosis (Zhao et al., 2025a). Additionally, nuclear receptor coactivator 4 (NCOA4) binds to ferritin and promotes ferritinophagy, releasing labile Fe²⁺ into the LIP and facilitating ferroptosis. Conversely, upregulation of FTL1 and ferritin heavy chain (FTH1), or inhibition of NCOA4, can suppress ferroptosis (Feng et al., 2024b). In an in vitro model of Erastin-induced ferroptosis in PC12 neuronal cells, the iron inhibitor curcumin–polydopamine nanoparticles (Cur-PDA NPs) markedly enhanced the chelation of Fe³⁺ and Fe²⁺, upregulated superoxide dismutase (SOD) and GSH expression, reduced Fe²⁺ and ROS levels, inhibited lipid peroxidation, restored mitochondrial function, and attenuated neuronal ferroptosis. These results suggest that iron chelators can mitigate neuronal damage by limiting iron-induced oxidative stress and ferroptosis (Lei et al., 2024). However, iron chelators including deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX) generally lack tissue and cellular specificity, often resulting in the non-selective depletion of physiologically essential iron. This indiscriminate iron removal disrupts vital intracellular iron-dependent processes, such as mitochondrial respiration, DNA synthesis and repair, and redox reactions (Peña-Montes et al., 2024; Calabrese et al., 2020; Prabhune and Ameen, 2025). Furthermore, certain chelators can disrupt iron-dependent neurophysiological processes, thereby further constraining their clinical applicability in NDDs (Marupudi and Xiong, 2024). Therefore, iron metabolism imbalance, primarily driven by iron overload, is regarded as a critical driver of ferroptosis. While regulation of iron metabolism-related proteins or the use of iron chelators can reduce intracellular labile Fe²⁺ levels and inhibit ferroptosis, current chelators lack tissue and cellular specificity and may interfere with neurophysiological functions, thereby limiting their clinical applicability.

System Xc⁻, GSH, and GPX4 constitute a critical signaling axis in the regulation of intracellular lipid peroxidation and ferroptosis (Yu et al., 2025). System Xc⁻ is a membrane-bound amino acid antiporter composed of solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2), connected via disulfide bonds. This transporter maintains the dynamic equilibrium between extracellular cystine and intracellular glutamate by importing cystine while exporting glutamate at a 1:1 ratio (Hu et al., 2025). Once inside the cell, cystine is reduced to cysteine through an NADPH-dependent process, serving as a key precursor for GSH synthesis and protecting against oxidative stress (Jiang and Sun, 2024). GSH, composed of glutamate, cysteine, and glycine, is a major intracellular antioxidant and exists in reduced GSH and oxidized glutathione (GSSG) forms (Yang et al., 2025). GPX4, a selenocysteine-containing enzyme, utilizes GSH to reduce toxic phospholipid hydroperoxides (PL-OOHs) to non-toxic phospholipid alcohols (PL-OHs), thereby disrupting lipid peroxidation chain reactions and preventing oxidative cell injury (Pontel et al., 2022). Dysfunction of System Xc⁻, depletion of GSH, or inhibition of GPX4 activity can lead to the accumulation of iron-dependent lipid peroxides, ultimately initiating ferroptosis (Guo et al., 2025a). Studies have confirmed that myricetin, a natural flavonoid, possesses multiple biological activities including antioxidant, anti-apoptotic, anti-inflammatory, and iron-chelating effects (Li et al., 2025a). Oral administration of myricetin significantly reduces Fe²⁺ levels in the substantia nigra of PD rats, inhibits neuronal ferroptosis, decreases ROS production, downregulates malondialdehyde (MDA) and α-synuclein (α-Syn) expression, elevates GSH levels, and ameliorates motor deficits. In vitro, myricetin treatment of SH-SY5Y neuroblastoma cells exposed to 1-methyl-4-phenylpyridine (MPP⁺) significantly reduces Fe²⁺ and ROS levels, activates the NRF2/GPX4 signaling pathway, suppresses neuronal ferroptosis, and mitigates cellular injury (Gu et al., 2024). Schisandrin B (Sch B), a natural lignan primarily derived from the traditional Chinese medicinal herb schisandra chinensis, exhibits anti-inflammatory, antioxidant, and neuroprotective properties (Dai et al., 2019). Administration of Sch B significantly inhibits glycogen synthase kinase 3β (GSK3β) activation in the hippocampus and cortex neurons of triple-transgenic Alzheimer’s disease (3 × Tg AD) mice, upregulates Nrf2, GPX4, and ferroptosis suppressor protein 1 (FSP1) expression, reduces levels of MDA, Fe²⁺, ROS, and tumor necrosis factor alpha (TNF-α), thereby suppressing neuronal ferroptosis and neuroinflammation and improving learning and memory performance. In vitro, Sch B suppresses erastin-induced ferroptosis in SH-SY5Y neuroblastoma cells by modulating the GSK3β/Nrf2/GPX4 signaling pathway (Ding et al., 2025). Moreover, radical-scavenging antioxidants such as Astragenol, Acteoside, and Edaravone have demonstrated neuroprotective effects in NDDs, primarily by neutralizing ROS, promoting GSH synthesis, and maintaining GPX4 activity to alleviate neuronal ferroptosis (Xiao et al., 2025; Wang et al., 2025a; Guo et al., 2023). However, the clinical efficacy of antioxidants remains controversial, mainly due to nonspecific mechanisms of action, insufficient target specificity, poor in vivo stability, and limited blood-brain barrier permeability (Ashok et al., 2022; Forman and Zhang, 2021). Therefore, GSH and GPX4, crucial regulators within the amino acid antioxidant system, play a critical role in inhibiting neuronal ferroptosis by maintaining their functional integrity. Although antioxidant therapies effectively inhibit ferroptosis, their clinical utility is limited by poor target specificity and instability. Thus, the development of highly specific drugs targeting key ferroptosis regulators is urgently needed.

Polyunsaturated fatty acids (PUFAs), which are major constituents of organelle membrane phospholipids, are particularly prone to peroxidation during ferroptosis (Han et al., 2025). Among PUFAs, arachidonic acid (AA) and adrenic acid (AdA) are primary substrates for lipid peroxidation. Their activation and incorporation into phospholipids are orchestrated by acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), two critical regulators of ferroptosis (Dixon et al., 2015; Poindessous et al., 2024). ACSL4 catalyzes the esterification of free AA and AdA with coenzyme A (CoA) to form PUFA-CoA derivatives (AA-CoA or AdA-CoA) (Doll et al., 2017). These activated fatty acyl-CoAs serve as acyl donors and are incorporated into lysophospholipids (Lyso-PLs), such as lysophosphatidylcholine (Lyso-PC) and lysophosphatidylethanolamine (Lyso-PE), by LPCAT3, yielding polyunsaturated fatty acid–containing phospholipids (PUFA-PLs) (Kagan et al., 2017; Liu et al., 2022a). Owing to their bis-allylic hydrogen atoms, PUFA-PLs are highly susceptible to peroxidation. This peroxidation occurs via two major pathways: the enzymatic pathway, mediated by lipoxygenases (LOXs), cytochrome P450 oxidoreductase (POR), and NADPH oxidases (NOXs), promotes the generation of PUFA-PL-OOHs, leading to the accumulation of reactive aldehydes, ketones, and other toxic metabolites, ultimately disrupting membrane integrity and triggering ferroptosis (Maheshwari, 2023); the non-enzymatic pathway involves ROS and Fe²⁺-driven Fenton reactions, which induce spontaneous oxidation of PUFA-PLs and further accumulation of PUFA-PL-OOHs (Kwun and Lee, 2023). Experimental evidence supports this mechanism. In a PD mouse model induced by intraperitoneal injection of salsolinol (SAL), and in SAL-treated SH-SY5Y cells, GSH expression was significantly reduced, whereas levels of ROS, Fe²⁺, ACSL4, MDA, 4-HNE, and α-Syn were markedly elevated. In addition, mitochondrial shrinkage and increased membrane density were observed, indicating that SAL induces ferroptosis and exacerbates neurotoxicity in both in vivo and in vitro PD models. Conversely, treatment with Ferrostatin-1 (Fer-1) or Acteoside, both ferroptosis inhibitors, significantly attenuated SAL-induced ferroptosis and neuronal injury (Wang et al., 2025b). These findings underscore lipid peroxide accumulation as a hallmark of ferroptosis, and suggest that downregulating ACSL4, LPCAT3, LOXs, or POR can suppress PUFA-PL-OOH formation and effectively inhibit ferroptosis.

Ferroptosis is regulated by multiple parallel and complementary pathways (Zhao et al., 2025c; Long et al., 2024), including the NADPH/FSP1/CoQ10 pathway, the dihydroorotate dehydrogenase (DHODH) pathway, the GTP cyclohydrolase 1 (GCH1)/tetrahydrobiopterin (BH4)/dihydrofolate reductase (DHFR) pathway, the membrane-bound O-acyltransferase 1/2 (MBOAT1/2) pathway, the peroxiredoxin 6 (PRDX6) pathway, and the 7-dehydrocholesterol (7-DHC) pathway. NADPH, a major cellular reductant, supports the enzymatic activity of FSP1, which resides on the plasma and outer mitochondrial membranes. FSP1 catalyzes the reduction of CoQ10 to CoQ10H₂, a lipophilic antioxidant that neutralizes PL-OOHs and halts lipid peroxidation, thereby suppressing ferroptosis independently of GPX4 (Doll et al., 2019; Bersuker et al., 2019; Chen et al., 2025b). DHODH, a mitochondrial inner membrane enzyme, catalyzes the oxidation of dihydroorotate (DHO) to orotate while transferring electrons to CoQ10, thereby generating CoQ10H₂ that scavenges ROS and phospholipid hydroperoxides (PL-OOHs) within mitochondria and prevents ferroptosis (Mao et al., 2021; Xiang et al., 2024). The GCH1/BH4/DHFR axis functions independently of GPX4 and contributes to antioxidant defense through the synthesis of BH4. As a redox-active cofactor, BH4 directly scavenges PL-OOHs and indirectly promotes CoQ10 biosynthesis, thus conferring resistance to ferroptosis (Du et al., 2024). Upon oxidation, BH4 is converted to BH2, which is recycled back to BH4 by DHFR; inhibition of DHFR sensitizes cells to ferroptosis (Wang et al., 2024). MBOAT1 and MBOAT2, newly identified negative regulators of ferroptosis, remodel membrane phospholipids to reduce their susceptibility to oxidation. Their expression is transcriptionally controlled by estrogen receptor (ER) and androgen receptor (AR), respectively (Liang et al., 2023). PRDX6 is a multifunctional antioxidant enzyme that exhibits a broad spectrum of catalytic activities. Through its peroxidase activity, PRDX6 directly reduces PL-OOHs, providing antioxidant defense even in the absence of GPX4. Additionally, PRDX6 acts as a selenium-binding protein that promotes efficient intracellular selenium utilization, thereby sustaining GPX4 expression and activity and indirectly enhancing resistance to ferroptosis (Ito et al., 2024). 7-DHC functions as an intrinsic inhibitor of ferroptosis by incorporating into cellular membranes and selectively neutralizing lipid peroxyl radicals via the conjugated double bonds in its B-ring. Through sacrificial oxidation, 7-DHC produces protective derivatives, such as 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), which disrupt lipid peroxidation chain reactions and mitigate ferroptosis (Freitas et al., 2024; Li et al., 2024b). Collectively, these parallel systems constitute a multi-tiered defense network that maintains redox balance and modulates ferroptosis sensitivity.

Human biospecimen analyses revealed elevated agrin expression, reduced levels of platelet-derived growth factor receptor beta (PDGFRβ), type IV collagen, and fibronectin, pronounced small artery atherosclerosis and venous collagen deposition, and a reduction in pericyte numbers in the brain tissue of AD patients. Notably, basement membrane–associated extracellular matrix remodeling was closely associated with neuropathological alterations in AD. In vitro experiments demonstrated that agrin treatment significantly downregulated PDGFRβ and claudin-5 expression in a blood-brain barrier co-culture model comprising human brain microvascular endothelial cells and pericytes, suggesting that agrin may induce pericyte death and impair the integrity of the blood-brain barrier. Moreover, agrin-treated pericytes exhibited elevated levels of ROS and Fe²⁺, along with reduced expression of GPX4 and FTH1, thereby promoting ferroptosis, suppressing pericyte proliferation, and compromising blood-brain barrier function. Notably, treatment with Fer-1, a ferroptosis inhibitor, significantly alleviated pericyte injury (Cao et al., 2025). In a co-culture model comprising neurons, astrocytes, and microglia derived from human induced pluripotent stem cells, exposure to iron and the ferroptosis inducer RSL3 demonstrated that microglia were the most susceptible to iron overload. FTH1 and lnterleukin-8 (IL-8) expression was markedly increased in microglia. Neurons showed reduced cell surface area, elevated lipid peroxidation, and characteristic features of ferroptosis. Notably, microglia removal significantly mitigated ferroptosis. Consistently, postmortem striatal brain tissue from three patients with PD exhibited elevated FTH1 and IL-8 expression, closely recapitulating the transcriptional profile of microglia in the in vitro model. Furthermore, genome-wide CRISPR screening identified SEC24 homolog B (SEC24B) as a key regulator of ferroptosis, and its knockout significantly inhibited ferroptosis in microglia (Ryan et al., 2023b). Experimental evidence demonstrated that stromal interaction molecule 1 (STIM1) expression was significantly downregulated in cortical neurons of mice with experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55. This downregulation facilitated the dissociation of STIM1 from STING, thereby activating the non-canonical STING signaling pathway and enhancing autophagy in cortical neurons. Increased colocalization of GPX4 with the autophagy marker microtubule-associated protein 1 light chain 3 (LC3) promoted autophagic degradation of GPX4. As a result, GPX4 and GSH levels were markedly reduced, accompanied by elevated ROS levels and increased lipid peroxidation, collectively driving ferroptosis in cortical neurons and leading to neurodegeneration. Neuron-specific STING knockout significantly attenuated neuronal damage in EAE mice. Notably, a similar phenomenon was observed in neurons from patients with MS, characterized by upregulated STING expression and markedly reduced STIM1 expression, suggesting that STIM1-STING-GPX4 axis-mediated ferroptosis is closely associated with neuronal injury in human MS pathology (Woo et al., 2024). In spinal cord tissues from patients with ALS, the expression of arachidonate 5-Lipoxygenase (ALOX5) and complement component 3 (C3) was markedly upregulated, accompanied by reduced GSH levels, elevated iron concentrations, and enhanced lipid peroxidation. Microglia in ALS spinal cords exhibited increased expression of ALOX5 and LPCAT3, indicating dysregulated iron metabolism and activation of ferroptosis. These alterations suggest that ferroptosis may contribute to the activation of neurotoxic glial cells and exacerbate neuronal damage in ALS. In a co-culture system of microglia, astrocytes, and neurons exposed to RSL3, ALOX5 was predominantly enriched in microglia. RSL3 stimulation elevated C3, IL-1α, and TNF-α levels in mixed glial cultures, while the ferroptosis inhibitor liproxstatin-1 effectively attenuated RSL3-induced neurotoxicity, supporting a role for ferroptotic stress in promoting neurotoxic glial activation. Consistently, SOD1^G93A transgenic mice exhibited ferroptotic features and neurotoxic glial activation resembling those observed in ALS patient spinal cords and in vitro models. Remarkably, treatment with CuII(atsm) significantly mitigated neuronal injury in the ALS mouse model (Liddell et al., 2024).

In summary, ferroptosis is intimately linked to the initiation and progression of AD, PD, MS, and ALS, as evidenced by strong concordance between findings from clinical human samples and those derived from animal and in vitro models. However, the majority of current clinical studies are still based on isolated case reports or small cohorts, limiting the ability to systematically characterize the prevalence and disease-stage- and population-specific features of ferroptosis.

Iron levels in specific organs such as the brain, skeletal muscles, intestines, and liver gradually increase with age (Chen and Xiao, 2014; Hashimoto et al., 2017). Abnormal iron accumulation induces neuronal ferroptosis and exacerbates oxidative damage, thereby contributing to the development and progression of NDDs (Dusek et al., 2022). Iron homeostasis is primarily maintained through the precise regulation of iron metabolism-related proteins (Ward et al., 2014). Dysregulation of these proteins disrupts systemic iron balance and induces neuronal damage (Ward et al., 2014). Six months of voluntary wheel running significantly downregulated the expression of Ferritin, HO-1, janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), DMT1, TFR, and hepcidin in the cerebral cortex of five familial Alzheimer’s disease (5×FAD) mice, reduced Aβ and IL-6 levels, inhibited Aβ plaque deposition and neuroinflammation, thereby improving neurological deficits in AD mice (Belaya et al., 2021). An 8-week treadmill exercise at 70%–85% VO₂max significantly downregulated the levels of TFR1, TF, DMT1, FTL, FTH, mitochondrial Ferritin, β-secretase, and APP in the cortical motor regions of aged amyloid precursor protein-C105 (APP-C105) mice, upregulated the expression of FPN1, Furin, and α-secretase, significantly reduced Fe²⁺, Fe³⁺, and total iron content, inhibited brain iron accumulation and Aβ plaque growth, thereby improving learning ability, memory, and cognitive function in aged APP-C105 mice (Choi et al., 2021). Fifty-five days of swimming training markedly activated the Akt signaling pathway in the skeletal muscle of SOD1^G93A transgenic mice, significantly reduced the expression of FTL, FTH, Ferritin, TFR1, and APP, upregulated FPN1 expression, inhibited Aβ and iron accumulation in skeletal muscle, and improved neural function in the mice. In vitro experiments demonstrated that Akt inhibition markedly upregulated the expression of FTL, FTH, TFR1, and Poly (rC)-binding protein 1 (PCBP1), downregulated FPN1 expression, increased APP expression, enhanced iron storage and uptake, and decreased iron efflux, thereby aggravating neurological injury in SH-SY5Y and C2C12 cells (Halon-Golabek et al., 2024). Therefore, exercise interventions may regulate iron metabolism-related protein expression, influence systemic iron homeostasis, and consequently delay the pathological progression of NDDs.

As a principal driver of ferroptosis, oxidative stress is defined as a physiological or pathological condition wherein the production of ROS and reactive nitrogen species (RNS) under endogenous or exogenous stimuli surpasses the neutralising capacity of the antioxidant defence system, thereby causing oxidative damage (Islam, 2017). Excessive iron accumulation in the brain intensifies oxidative stress, amplifies lipid peroxidation, and promotes ferroptosis, thereby accelerating neuronal degeneration (Zhang et al., 2024). Eight weeks of aerobic exercise significantly activated the System Xc⁻/GPx4 signaling pathway in the prefrontal cortex of APPswe/PS1dE9 transgenic AD mice, up-regulated FTL and BACE1 expression, significantly downregulated 4-HNE levels, inhibited oxidative stress, lipid peroxidation, and ferroptosis, reduced Aβ positivity, alleviated neuronal morphological abnormalities, and improved learning and memory functions in AD mice (Li et al., 2024a). Four weeks of moderate-intensity treadmill exercise significantly inhibited the activation of the STING signaling pathway in the damaged cortex of traumatic brain injury mice, downregulated the expression of TFR1, FTH, and ACSL4, upregulated FPN, System Xc⁻, GPX4, and GSH expression, and reduced levels of 4-HNE, MDA, and Fe²⁺. This intervention alleviated abnormalities in iron homeostasis, lipid peroxidation, and antioxidant system damage, inhibited ferroptosis, and improved neurological damage and cognitive dysfunction. Additionally, overexpression of STING reversed the inhibitory effect of exercise on ferroptosis, thereby exacerbating neurological damage (Chen et al., 2023). Fourteen days of treadmill training significantly enhanced the expression of NRF2, GPX4, and SLC7A11 in the cerebral cortex of rats with cerebral ischemia-reperfusion injury. It activated the SLC7A11/GPX4 signaling pathway, upregulated GSH-Px and GSH expression, decreased MDA and ferroptosis levels, and inhibited lipid peroxidation and ferroptosis in the cerebral cortex, thereby improving motor function, balance, and neurological deficits in the rats. Erastin, a ferroptosis activator, significantly attenuated the neuroprotective effects of treadmill training in rats with cerebral ischemia-reperfusion injury (Liu et al., 2022b). Therefore, aerobic exercise can modulate oxidative stress in brain tissue, inhibit lipid peroxidation and ferroptosis, and mitigate neurological deficits.

Exerkines are bioactive molecules secreted by exercise-stimulated tissues such as skeletal muscle, adipose tissue, liver, brain, and other organs, including myokines, cardiokines, hepatokines, adipokines, neurokines, lactate, and miRNAs. These exerkines act through autocrine, paracrine, or endocrine mechanisms to mediate inter-organ communication, playing essential roles in regulating nervous system function, attenuating neuroinflammation, and promoting neural repair (Chow et al., 2022; Pedersen and Fischer, 2007). Studies have confirmed that Irisin is a protein-like myokine secreted during exercise, derived from fibronectin type III domain-containing protein 5 (FNDC5) (Ma et al., 2025; Akbulut et al., 2025). Irisin-loaded bone marrow mesenchymal stem cell-derived exosomes significantly downregulated the expression of Yes-associated protein (YAP), early growth response 1 (EGR1), and ACSL4, inhibited activation of the YAP/EGR1/ACSL4 signaling pathway, significantly increased GSH levels, decreased levels of Fe²⁺, lactate dehydrogenase (LDH), MDA, and lipid ROS, inhibited neuronal ferroptosis and lipid peroxidation, thereby ameliorating oxygen-glucose deprivation and reoxygenation (OGD/R)-induced neuronal injury. In vivo experiments further demonstrated that Irisin-loaded bone marrow mesenchymal stem cell-derived exosomes significantly inhibited activation of the YAP/EGR1/ACSL4 signaling pathway in the brains of middle cerebral artery occlusion (MCAO) mice, suppressed ferroptosis and lipid peroxidation, thereby mitigating ischemic brain injury (Fang et al., 2025). Six weeks of aerobic exercise significantly upregulated the expression of fibroblast growth factor 21 (FGF21), FGFR1, and peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) in the paraventricular nucleus of mice with myocardial ischemia/reperfusion injury, increased the phosphorylated AMP-activated protein kinase alpha (p-AMPKα)/AMPKα ratio, upregulated the expression of SOD1, SOD2, and sestrin 2 (SESN2), reduced ROS levels, downregulated the expression of TFR1 and FTH, upregulated the expression of FPN1, suppressed neuronal oxidative stress and ferroptosis, thereby ameliorating neuronal injury in mice with myocardial ischemia/reperfusion injury. In vitro experiments further confirmed that FGF21 protected HT22 cells from OGD/R-induced oxidative stress and ferroptosis, thereby attenuating neuronal injury (Zhao et al., 2025c). OGD-induced ACSL4 expression was significantly elevated, while the expression of GPX4 and SLC7A11 was significantly reduced in PC12 cells. Furthermore, ROS and LDH levels were increased, promoting ferroptosis in PC12 cells. In vivo experiments confirmed that 4 weeks of aerobic training significantly increased the expression of exosome miR-484 in the skeletal muscle of ischemic stroke rats. Exosome miR-484 in skeletal muscle was found to target and downregulate ACSL4 expression, upregulate GPX4 and SLC7A11 expression in brain tissue, inhibit neuronal ferroptosis and lipid peroxidation, and promote nerve repair (Huang et al., 2024). Therefore, exercise regulates the expression of various exerkines, inhibits neuronal ferroptosis, and exerts neuroprotective effects.