From scavenger to victim: mechanism and treatment of microglial ferroptosis in white matter injury disease
6 affiliations
- 1School of Basic Medical Sciences, Hubei University of Chinese Medicine , , ,
- 2The First Clinical Medical School, Hubei University of Chinese Medicine , , ,
- 3Hubei Shizhen Laboratory Department of Geriatrics & Department of Orthopedic Surgery , , ,
- 4Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine , , ,
- 5The First People’s Hospital of Jingzhou (Jingzhou First People’s Hospital) , , ,
- 6Xiangyang Hospital of Integrated Traditional Chinese and Western Medicine , , ,
Abstract
Failure of myelin repair is a shared pathological feature of white matter injury (WMI)-associated diseases, including Alzheimer’s disease (AD), vascular dementia (VaD), and multiple sclerosis (MS), but the underlying mechanisms remain incompletely understood. Microglia, the resident innate immune cells of the central nervous system (CNS), contribute to white matter homeostasis by clearing myelin debris and supporting remyelination. Within the iron- and lipid-rich white matter microenvironment, sustained uptake of myelin and oligodendroglial debris may impose phagocytic and metabolic stress on microglia, thereby increasing their susceptibility to ferroptosis, an iron-dependent form of regulated cell death driven by membrane phospholipid peroxidation. This susceptibility is regulated by interconnected mechanisms involving ferritinophagy-associated iron dysregulation, ACSL4/NOX2/15-LOX-related lipid peroxidation, and impaired endogenous ferroptosis-defense systems. Microglial responses are also heterogeneous: disease-associated, demyelination-associated, white matter-associated, lipid-droplet-accumulating, and degenerative microglial programs represent partially overlapping and context-dependent states rather than a proven linear trajectory. In susceptible microglial subsets, ferroptosis or ferroptosis-associated dysfunction may impair debris clearance and trophic support while promoting oxidized lipid accumulation and inflammatory signaling, thereby limiting remyelination. This review summarizes current evidence on the molecular mechanisms, multicellular interactions, microglial states, disease contexts, and therapeutic strategies associated with microglial ferroptosis in WMI. We further propose a functional therapeutic-window framework based on phagocytic competence, iron–lipid handling capacity, antioxidant reserve, and evidence of ferroptotic injury, and discuss major challenges in clinical translation. Overall, current evidence supports microglial ferroptosis as a context-dependent contributor to myelin repair failure rather than a universal determinant.
Related
- ZFP36L1 Enhances Microglial Ferroptosis in Ischemic Stroke by Reducing FTO‐Mediated N6‐Methyladenosine Demethylation of ACSL1 mRNA
- Hippo pathway in cancer ferroptosis: from mechanism insights to targeted therapies
- Microglial Foxo3 shapes dopaminergic vulnerability in Parkinson’s disease
- Comparative transcriptomic analysis reveals the protective mechanism of ferulic acid against lipopolysaccharide-induced ferroptosis in IPEC-J2 cells
- Microglial Therapeutic Potential in Alzheimer's Disease: From Phenotypic Diversity to Targeted Interventions.
BibTeX
@article{wang2026from,
title = {{From scavenger to victim: mechanism and treatment of microglial ferroptosis in white matter injury disease}},
author = {Ruoyu Wang and Qiong Yang and Zheng Cao and Jianjie Zhou and Bingxin Tian and Xin Wang and Xiaohong Zhang and Qingwei Xiang and Gang Chen},
journal = {Frontiers in immunology},
year = {2026},
month = sep,
doi = {10.3389/fimmu.2026.1859981},
url = {https://europepmc.org/article/PMC/PMC13662909},
note = {CC BY},
}
RIS
TY - JOUR
TI - From scavenger to victim: mechanism and treatment of microglial ferroptosis in white matter injury disease
AU - Ruoyu Wang
AU - Qiong Yang
AU - Zheng Cao
AU - Jianjie Zhou
AU - Bingxin Tian
AU - Xin Wang
AU - Xiaohong Zhang
AU - Qingwei Xiang
AU - Gang Chen
PY - 2026
DA - 2026/09/30
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1859981
UR - https://europepmc.org/article/PMC/PMC13662909
AB - Failure of myelin repair is a shared pathological feature of white matter injury (WMI)-associated diseases, including Alzheimer’s disease (AD), vascular dementia (VaD), and multiple sclerosis (MS), but the underlying mechanisms remain incompletely understood. Microglia, the resident innate immune cells of the central nervous system (CNS), contribute to white matter homeostasis by clearing myelin debris and supporting remyelination. Within the iron- and lipid-rich white matter microenvironment, sustained uptake of myelin and oligodendroglial debris may impose phagocytic and metabolic stress on microglia, thereby increasing their susceptibility to ferroptosis, an iron-dependent form of regulated cell death driven by membrane phospholipid peroxidation. This susceptibility is regulated by interconnected mechanisms involving ferritinophagy-associated iron dysregulation, ACSL4/NOX2/15-LOX-related lipid peroxidation, and impaired endogenous ferroptosis-defense systems. Microglial responses are also heterogeneous: disease-associated, demyelination-associated, white matter-associated, lipid-droplet-accumulating, and degenerative microglial programs represent partially overlapping and context-dependent states rather than a proven linear trajectory. In susceptible microglial subsets, ferroptosis or ferroptosis-associated dysfunction may impair debris clearance and trophic support while promoting oxidized lipid accumulation and inflammatory signaling, thereby limiting remyelination. This review summarizes current evidence on the molecular mechanisms, multicellular interactions, microglial states, disease contexts, and therapeutic strategies associated with microglial ferroptosis in WMI. We further propose a functional therapeutic-window framework based on phagocytic competence, iron–lipid handling capacity, antioxidant reserve, and evidence of ferroptotic injury, and discuss major challenges in clinical translation. Overall, current evidence supports microglial ferroptosis as a context-dependent contributor to myelin repair failure rather than a universal determinant.
SN - 1664-3224
ER -