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Peer-reviewedCC BY-NC-ND 4.0Cellular and Molecular Neurobiology

Ferroptosis Targeting: A Novel Therapeutic Strategy Against Anesthetic-Induced Neurotoxicity

  • Wenxin Feng1
  • Zhiji Wang2
  • Xia Yun3
  • Hongquan Wang2,4
  • Shuang Wu5,6
  • Lida Du7
7 affiliations
  1. 1Department of Anesthesiology, Basic Medical College, Guangxi Medical University, Nanning, China
  2. 2Department of Neurology, Hohhot First Hospital, Fifth Clinical Medical College, Inner Mongolia Medical University, Hohhot, China
  3. 3Teaching Department, Hohhot First Hospital, Fifth Clinical Medical College, Inner Mongolia Medical University, Hohhot, China
  4. 4Department of Geriatrics, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, China
  5. 5Department of Neurology, Zhongnan Hospital of Wuhan University, No.169 Donghu Street, Wuhan, 430071 Hubei China
  6. 6Hubei Provincial Clinical Research Center for Dementia and Cognitive Impairment, No.169 Donghu Street, Wuhan, 430071 Hubei China
  7. 7Division of Neurobiology, Johns Hopkins University, Baltimore, MD 21205 USA
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Abstract

Anesthetic-induced neurotoxicity (AIN), particularly postoperative cognitive dysfunction and related perioperative neurocognitive disorders, remains a significant clinical challenge. Ferroptosis—an iron-dependent, lipid peroxidation-driven regulated cell death—has emerged as a key mechanism in preclinical models of anesthetic neurotoxicity. However, administration contexts (e.g., developmental, aged, spinal, or ototoxic) differ in patient populations, exposure paradigms, and tissue -specific outcomes. Preclinical evidence indicates that anesthetics like propofol, sevoflurane, and isoflurane trigger ferroptosis via iron dysregulation, antioxidant depletion, and lethal lipid peroxidation, contributing to neuronal injury and cognitive decline.Pharmacological inhibition of ferroptosis-associated pathways confers neuroprotection in these experimental models, although these findings remain strictly preclinical and do not establish clinical efficacy. This review first outlines core ferroptosis mechanisms, then details the distinct molecular pathways by which various anesthetics induce ferroptosis, and finally summarizes recent advances in ferroptosis-targeted neuroprotection. Crucially, all current evidence is derived exclusively from preclinical studies; clinical translation remains to be established. Moreover, ferroptosis’s relative contribution versus other cell death pathways likely varies across developmental stages, tissue types, and exposure conditions. Nonetheless, targeting ferroptosis represents a promising therapeutic strategy that warrants further investigation in well-designed translational studies to assess its potential for mitigating AIN across diverse clinical contexts.

Graphical Abstract: Targeting ferroptosis in anesthetic neurotoxicity: anesthetics trigger ferroptosis via iron overload, GPX4/GSH depletion, and lipid peroxidation, driving cognitive dysfunction. Pharmacological ferroptosis inhibition (e.g., Fer-1, Liproxstatin-1) blocks this cascade, offering neuroprotection against anesthetic-induced neurotoxicity.

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Cite

BibTeXRIS
BibTeX
@article{feng2026ferroptosis,
  title = {{Ferroptosis Targeting: A Novel Therapeutic Strategy Against Anesthetic-Induced Neurotoxicity}},
  author = {Wenxin Feng and Zhiji Wang and Xia Yun and Hongquan Wang and Shuang Wu and Lida Du},
  journal = {Cellular and Molecular Neurobiology},
  year = {2026},
  month = aug,
  doi = {10.1007/s10571-026-01806-7},
  url = {https://doi.org/10.1007/s10571-026-01806-7},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Ferroptosis Targeting: A Novel Therapeutic Strategy Against Anesthetic-Induced Neurotoxicity
AU  - Wenxin Feng
AU  - Zhiji Wang
AU  - Xia Yun
AU  - Hongquan Wang
AU  - Shuang Wu
AU  - Lida Du
PY  - 2026
DA  - 2026/08/13
JO  - Cellular and Molecular Neurobiology
DO  - 10.1007/s10571-026-01806-7
UR  - https://doi.org/10.1007/s10571-026-01806-7
AB  - Anesthetic-induced neurotoxicity (AIN), particularly postoperative cognitive dysfunction and related perioperative neurocognitive disorders, remains a significant clinical challenge. Ferroptosis—an iron-dependent, lipid peroxidation-driven regulated cell death—has emerged as a key mechanism in preclinical models of anesthetic neurotoxicity. However, administration contexts (e.g., developmental, aged, spinal, or ototoxic) differ in patient populations, exposure paradigms, and tissue -specific outcomes. Preclinical evidence indicates that anesthetics like propofol, sevoflurane, and isoflurane trigger ferroptosis via iron dysregulation, antioxidant depletion, and lethal lipid peroxidation, contributing to neuronal injury and cognitive decline.Pharmacological inhibition of ferroptosis-associated pathways confers neuroprotection in these experimental models, although these findings remain strictly preclinical and do not establish clinical efficacy. This review first outlines core ferroptosis mechanisms, then details the distinct molecular pathways by which various anesthetics induce ferroptosis, and finally summarizes recent advances in ferroptosis-targeted neuroprotection. Crucially, all current evidence is derived exclusively from preclinical studies; clinical translation remains to be established. Moreover, ferroptosis’s relative contribution versus other cell death pathways likely varies across developmental stages, tissue types, and exposure conditions. Nonetheless, targeting ferroptosis represents a promising therapeutic strategy that warrants further investigation in well-designed translational studies to assess its potential for mitigating AIN across diverse clinical contexts.  Graphical Abstract: Targeting ferroptosis in anesthetic neurotoxicity: anesthetics trigger ferroptosis via iron overload, GPX4/GSH depletion, and lipid peroxidation, driving cognitive dysfunction. Pharmacological ferroptosis inhibition (e.g., Fer-1, Liproxstatin-1) blocks this cascade, offering neuroprotection against anesthetic-induced neurotoxicity.
SN  - 0272-4340
SN  - 1573-6830
ER  -