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已发表论文
麻醉诱导的铁死亡：心脑损伤中的双向调节及分子机制
Authors Chen Y , Ouyang J , Zhao W, Cheng L, Ye X, Hu Y, Si Y, Niu Q , Zhang H, Qiao Q, Zhang J
Received 11 July 2025
Accepted for publication 9 November 2025
Published 17 November 2025 Volume 2025:18 Pages 16023—16043
DOI https://doi.org/10.2147/JIR.S553229
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Qing Lin
Ying Chen,1,2,* Jie Ouyang,2,* Weili Zhao,2 Lu Cheng,3– 5 Xuerui Ye,3– 5 Yong Hu,3– 5 Yongyu Si,2 Qin Niu,2 Haoling Zhang,6 Qian Qiao,3– 5 Jingjing Zhang3– 5
1Department of Anesthesiology, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China; 2Department of Anesthesiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650000, People’s Republic of China; 3Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, 650000, People’s Republic of China; 4Yunnan Provincial Cardiovascular Clinical Medical Center, Kunming, 650000, People’s Republic of China; 5Yunnan Provincial Cardiovascular Clinical Medical Research Center, Kunming, 650000, People’s Republic of China; 6Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang, 13200, Malaysia
*These authors contributed equally to this work
Correspondence: Jingjing Zhang, Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, Affiliated Cardiovascular Hospital of Kunming Medical University/Yunnan Provincial Cardiovascular Clinical Medical Center/Yunnan Provincial Cardiovascular Clinical Medical Research Center, Kunming, Yunnan Province, 650000, People’s Republic of China, Email zhangjingjing1@kmmu.edu.cn Haoling Zhang, Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang, 13200, Malaysia, Email zhanghaolingedu@163.com
Abstract: Perioperative use of common anesthetics—including sevoflurane, propofol, and dexmedetomidine—may induce cardio-cerebral injury via ferroptosis, an iron-dependent form of cell death. We introduce the “Molecular Switches”, proposing that these drugs act as tissue-specific switches regulating ferroptosis bidirectionally. Their effect (promote or inhibit) depends critically on local factors: receptor expression profiles, metabolic status, baseline redox tone, and post-translational modifications of key proteins like glutathione peroxidase 4 (GPX4). High-risk organs like heart and brain, characterized by elevated metabolic demands, polyunsaturated fatty acid (PUFA)-rich membranes, and stringent iron homeostasis, express unique molecular switch configurations explaining their susceptibility. During ischemia-reperfusion injury (IRI), leveraging this principle allows protective anesthetic strategies: targeting the nuclear factor erythroid 2–related factor 2 (Nrf2)/GPX4/solute carrier family 7 member 11 (SLC7A11) antioxidant axis enhances endogenous defenses, while inhibiting Acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated lipid peroxidation limits damage initiation. Crucially, effective myocardial protection prioritizes mitochondrial function recovery and iron efflux modulation, whereas cerebroprotection centers on preserving neuronal iron homeostasis and blood-brain barrier (BBB) integrity—distinct applications derived directly from understanding tissue-specific molecular switches. Addressing clinical translation challenges (limited drug specificity, complex polypharmacy effects, biomarker gaps), we advocate for developing personalized anesthetic protocols informed by molecular switch profiling, employing nanocarriers for targeted delivery across the BBB, and establishing AI-driven predictive models based on ferroptosis biomarkers. This framework provides novel insights for optimizing perioperative cardio-cerebral protection.
Keywords: anesthetics, ferroptosis, cardio-cerebral injury, molecular switches, ischemia-reperfusion injury, bidirectional regulation
1Department of Anesthesiology, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China; 2Department of Anesthesiology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650000, People’s Republic of China; 3Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, 650000, People’s Republic of China; 4Yunnan Provincial Cardiovascular Clinical Medical Center, Kunming, 650000, People’s Republic of China; 5Yunnan Provincial Cardiovascular Clinical Medical Research Center, Kunming, 650000, People’s Republic of China; 6Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang, 13200, Malaysia
*These authors contributed equally to this work
Correspondence: Jingjing Zhang, Department of Cardiovascular Medicine, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, Affiliated Cardiovascular Hospital of Kunming Medical University/Yunnan Provincial Cardiovascular Clinical Medical Center/Yunnan Provincial Cardiovascular Clinical Medical Research Center, Kunming, Yunnan Province, 650000, People’s Republic of China, Email zhangjingjing1@kmmu.edu.cn Haoling Zhang, Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang, 13200, Malaysia, Email zhanghaolingedu@163.com
Abstract: Perioperative use of common anesthetics—including sevoflurane, propofol, and dexmedetomidine—may induce cardio-cerebral injury via ferroptosis, an iron-dependent form of cell death. We introduce the “Molecular Switches”, proposing that these drugs act as tissue-specific switches regulating ferroptosis bidirectionally. Their effect (promote or inhibit) depends critically on local factors: receptor expression profiles, metabolic status, baseline redox tone, and post-translational modifications of key proteins like glutathione peroxidase 4 (GPX4). High-risk organs like heart and brain, characterized by elevated metabolic demands, polyunsaturated fatty acid (PUFA)-rich membranes, and stringent iron homeostasis, express unique molecular switch configurations explaining their susceptibility. During ischemia-reperfusion injury (IRI), leveraging this principle allows protective anesthetic strategies: targeting the nuclear factor erythroid 2–related factor 2 (Nrf2)/GPX4/solute carrier family 7 member 11 (SLC7A11) antioxidant axis enhances endogenous defenses, while inhibiting Acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated lipid peroxidation limits damage initiation. Crucially, effective myocardial protection prioritizes mitochondrial function recovery and iron efflux modulation, whereas cerebroprotection centers on preserving neuronal iron homeostasis and blood-brain barrier (BBB) integrity—distinct applications derived directly from understanding tissue-specific molecular switches. Addressing clinical translation challenges (limited drug specificity, complex polypharmacy effects, biomarker gaps), we advocate for developing personalized anesthetic protocols informed by molecular switch profiling, employing nanocarriers for targeted delivery across the BBB, and establishing AI-driven predictive models based on ferroptosis biomarkers. This framework provides novel insights for optimizing perioperative cardio-cerebral protection.
Keywords: anesthetics, ferroptosis, cardio-cerebral injury, molecular switches, ischemia-reperfusion injury, bidirectional regulation