# Research Progress of Ferroptosis in Cerebral Infarction

## TL;DR

This paper reviews how a type of cell death called ferroptosis contributes to brain injury after stroke and explores new treatment strategies to prevent it.

## Contribution

The paper provides a comprehensive review of ferroptosis mechanisms and emerging therapies in cerebral infarction, highlighting translational opportunities.

## Key findings

- Ferroptosis in cerebral infarction is driven by glutathione depletion, GPX4 inactivation, and iron-catalyzed lipid peroxidation.
- Therapeutic strategies like ferroptosis inhibitors, iron chelators, and RNA/gene-targeted interventions show strong neuroprotection in preclinical models.
- Biomarkers such as oxylipins and GPX4 fragments may help identify patients who could benefit from ferroptosis-targeted therapies.

## Abstract

Purpose: To synthesize current mechanistic insights and translational progress on ferroptosis, a regulated, iron‐dependent, nonapoptotic cell death pathway in the pathophysiology and treatment of cerebral infarction (ischemic stroke), and to outline therapeutic opportunities and remaining gaps for clinical application.

Method: Narrative, focused review of preclinical and translational studies (in vitro, ex vivo, and in vivo ischemia/reperfusion and middle cerebral artery occlusion models), alongside emerging biomarker, nanocarrier, and gene/RNA‐based strategies reported up to 2025. Evidence was organized across five domains: (1) redox and lipid peroxidation biology; (2) iron metabolism and ferritinophagy; (3) mitochondrial dysfunction; (4) neuroinflammation and blood–brain barrier integrity; and (5) therapeutic development and early clinical exploration.

Finding: Ferroptosis in cerebral infarction is driven by glutathione depletion, glutathione peroxidase‐4 (GPX4) inactivation, and iron‐catalyzed lipid peroxidation of polyunsaturated phospholipids, with acyl‐CoA synthetase long‐chain family member‐4 (ACSL4) and lysophosphatidylcholine acyltransferase‐3 (LPCAT3) priming membranes for oxidative injury. Mitochondrial reactive oxygen species, iron–sulfur cluster instability, and cardiolipin oxidation amplify ferroptotic signaling, while ferroptosis–inflammation crosstalk (via damage‐associated molecular patterns and microglial activation) aggravates secondary injury and blood–brain barrier disruption. Candidate biomarkers (e.g., oxylipins, 8‐iso‐prostaglandin F2α, GPX4 fragments; gene pairs such as CDKN1A/JUN; NFE2L2 pathway readouts) show promise for patient stratification. Pharmacological approaches—including radical‐trapping antioxidants (ferrostatin‐1, liproxstatin‐1), iron chelation, and nuclear factor erythroid 2–related factor 2 (Nrf2) activation—consistently reduce infarct volume and improve function in animal models. Nanoparticle formulations enhance brain delivery of ferroptosis modulators, and RNA/gene‐targeted strategies (e.g., SLC7A11/GPX4/FSP1 axes; exosomal noncoding RNAs) expand the therapeutic toolkit. Clinically, iron‐modulating strategies in ischemic stroke suggest feasibility; however, dedicated, biomarker‐guided ferroptosis trials remain limited.

Conclusion: Ferroptosis represents a convergent, actionable mechanism of ischemic neuronal death and secondary brain injury. Multimodal interventions that combine lipid peroxidation control, iron homeostasis, mitochondrial protection, and inflammation resolution are biologically compelling. Key next steps include: validating real‐time biomarkers for patient selection and timing; optimizing brain‐penetrant delivery systems; integrating ferroptosis modulation with reperfusion therapies; and advancing rigorously designed phase II/III trials to establish efficacy and safety in defined stroke subtypes.

Cerebral infarction triggers ischemia–reperfusion injury, leading to iron overload, oxidative stress, and mitochondrial dysfunction, which together initiate ferroptosis—an iron‐dependent, lipid peroxidation–driven form of neuronal death. Disruption of the System Xc−/GSH/GPX4 antioxidant axis and ACSL4‐mediated PUFA phospholipid enrichment accelerates membrane peroxidation. Ferroptotic neurons release DAMPs that activate microglia, amplify inflammation, disrupt the blood–brain barrier, and worsen secondary brain injury. Therapeutic strategies—including ferroptosis inhibitors, iron chelators, Nrf2 activators, nanocarrier‐based delivery systems, and RNA/gene‐targeted interventions—demonstrate strong neuroprotection in preclinical stroke models, offering promising translational potential for reducing infarct volume and improving functional outcome.