Mitochondria-associated ferroptosis in ischemic stroke: Pathophysiological evolution, interorganelle crosstalk, and therapeutic targeting
5 affiliations
- 1School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Hunan Province Key Laboratory of Cerebrovascular Disease Prevention and Treatment of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
- 2The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310000, China
- 3School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
- 4Hunan Province Key Laboratory of Cerebrovascular Disease Prevention and Treatment of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
- 5School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China; Corresponding author.
Abstract
Ischemic stroke (IS) results from an acute interruption of cerebral blood flow and the ensuing collapse of energy metabolism. Although vascular recanalization can salvage the ischemic penumbra, its overall benefit remains constrained by a narrow therapeutic window and reperfusion injury. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, contributes to neuronal injury after IS and can amplify ischemia/reperfusion injury. By integrating energy metabolism, iron homeostasis, and redox balance, mitochondria can shape ferroptosis susceptibility within the energy-depleted, iron-dysregulated, and oxidatively stressed ischemic brain. However, most studies have examined iron metabolism and lipid peroxidation at the whole-cell level, leaving the temporal and interorganelle dimensions of mitochondrial regulation of ferroptosis insufficiently integrated. Here, we organize mitochondria-associated ferroptosis across the pathological course of IS, from metabolic reprogramming and substrate accumulation during ischemia to the reverse electron transport-associated reactive oxygen species burst during early reperfusion and subsequent disruption of mitochondrial quality control. We further examine mitochondrial crosstalk with the endoplasmic reticulum, lysosomes, lipid droplets, and nucleus, compare ferroptosis susceptibility across neurovascular unit cell populations, and map these mechanisms onto pharmacological interventions and mechanistically plausible therapeutic windows. Finally, we assess barriers to the clinical translation of mitochondria-targeted therapies and provide a stage-resolved framework for developing neuroprotective strategies in IS.
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BibTeX
@article{zhang2026mitochondriaassociated,
title = {{Mitochondria-associated ferroptosis in ischemic stroke: Pathophysiological evolution, interorganelle crosstalk, and therapeutic targeting}},
author = {Mengge Zhang and Yuzhe Cai and Qianru Zeng and Yunhao Yi and Jing Liu and Fang Lei and Ruiyu Huang and Zhenghao Cai and Yanling Chen and Yihui Deng},
journal = {Pharmacological Research},
year = {2026},
month = nov,
doi = {10.1016/j.phrs.2026.109662},
url = {https://doi.org/10.1016/j.phrs.2026.109662},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mitochondria-associated ferroptosis in ischemic stroke: Pathophysiological evolution, interorganelle crosstalk, and therapeutic targeting
AU - Mengge Zhang
AU - Yuzhe Cai
AU - Qianru Zeng
AU - Yunhao Yi
AU - Jing Liu
AU - Fang Lei
AU - Ruiyu Huang
AU - Zhenghao Cai
AU - Yanling Chen
AU - Yihui Deng
PY - 2026
DA - 2026/11/04
JO - Pharmacological Research
DO - 10.1016/j.phrs.2026.109662
UR - https://doi.org/10.1016/j.phrs.2026.109662
AB - Ischemic stroke (IS) results from an acute interruption of cerebral blood flow and the ensuing collapse of energy metabolism. Although vascular recanalization can salvage the ischemic penumbra, its overall benefit remains constrained by a narrow therapeutic window and reperfusion injury. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, contributes to neuronal injury after IS and can amplify ischemia/reperfusion injury. By integrating energy metabolism, iron homeostasis, and redox balance, mitochondria can shape ferroptosis susceptibility within the energy-depleted, iron-dysregulated, and oxidatively stressed ischemic brain. However, most studies have examined iron metabolism and lipid peroxidation at the whole-cell level, leaving the temporal and interorganelle dimensions of mitochondrial regulation of ferroptosis insufficiently integrated. Here, we organize mitochondria-associated ferroptosis across the pathological course of IS, from metabolic reprogramming and substrate accumulation during ischemia to the reverse electron transport-associated reactive oxygen species burst during early reperfusion and subsequent disruption of mitochondrial quality control. We further examine mitochondrial crosstalk with the endoplasmic reticulum, lysosomes, lipid droplets, and nucleus, compare ferroptosis susceptibility across neurovascular unit cell populations, and map these mechanisms onto pharmacological interventions and mechanistically plausible therapeutic windows. Finally, we assess barriers to the clinical translation of mitochondria-targeted therapies and provide a stage-resolved framework for developing neuroprotective strategies in IS.
SN - 1096-1186
ER -