Molecular mechanisms and therapeutic strategies of endoplasmic reticulum stress-mediated hepatic ischemia-reperfusion injury
- Journal of Chongqing Medical University Vol. 50, Issue 7, Pages: 951-956(2025)
- 作者机构：
1.重庆医科大学附属璧山医院肝胆外科，重庆 402760
2.重庆医科大学附属璧山医院人事部，重庆 402760
- 作者简介：
- 基金信息：
DOI：10.13406/j.cnki.cyxb.003823
CLC： K658.5Received：26 December 2024，
Revised：2025-03-04，
Accepted：17 March 2025，
Published：28 July 2025
- 稿件说明：
移动端阅览
刘畅,陶锐,胡启辉,等.内质网应激介导的肝缺血再灌注损伤的分子机制与治疗策略[J].重庆医科大学学报,2025,50(7):951-956.
Liu Chang¹,Tao Rui,Hu Qihui,et al.Molecular mechanisms and therapeutic strategies of endoplasmic reticulum stress-mediated hepatic ischemia-reperfusion injury[J].Journal of Chongqing Medical University,2025,50(7):951-956.
刘畅,陶锐,胡启辉,等.内质网应激介导的肝缺血再灌注损伤的分子机制与治疗策略[J].重庆医科大学学报,2025,50(7):951-956. DOI： 10.13406/j.cnki.cyxb.003823.
Liu Chang¹,Tao Rui,Hu Qihui,et al.Molecular mechanisms and therapeutic strategies of endoplasmic reticulum stress-mediated hepatic ischemia-reperfusion injury[J].Journal of Chongqing Medical University,2025,50(7):951-956. DOI： 10.13406/j.cnki.cyxb.003823.
摘要
肝缺血再灌注（ischemia-reperfusion，IRI）是肝脏手术和移植过程中常见的病理现象，导致严重的组织损伤和功能障碍。其机制复杂，涉及氧化应激、炎症反应及钙离子稳态紊乱等多种因素。近年来，内质网应激（endoplasmic reticulum stress，ERS）在IRI中的作用逐渐受到关注。ERS通过未折叠蛋白反应（unfolded protein response，UPR）激活蛋白激酶R样内质网激酶（protein kinase r-like endoplasmic reticulum kinase，PERK）、肌醇需求酶1（inositol-requiring enzyme 1，IRE1）和激活转录因子6（activating transcription factor 6，ATF6）3条经典信号通路，初期旨在恢复内质网稳态并保护细胞。然而，当应激反应过度或持续时，ERS可转向激活凋亡通路如增强子结合蛋白同源蛋白（CCAAT/enhancer-binding protein homologous protein，CHOP）、Bcl-2相关X蛋白/Bcl-2同源拮抗剂杀伤蛋白（bcl-2-associated X protein/bcl-2 homologous antagonist killer，Bax/Bak），加剧细胞损伤。此外，ERS与自噬和氧化应激等其他细胞应激反应密切相关，共同影响肝细胞的生存与死亡。调控ERS，尤其是针对UPR3条通路的干预，被认为是减轻肝IRI的潜在治疗途径。药物干预（如4-苯基丁酸、牛磺胆酸）和基因治疗（如敲除PERK或IRE1）在抑制ERS的同时，显示出保护肝功能的积极效果。本文综述了ERS在肝缺血再灌注损伤中的作用机制，重点探讨了UPR 3条通路的具体功能及其作为治疗靶点的潜力，并展望了相关治疗策略的研究前景。
Abstract
Hepatic ischemia-reperfusion injury（IRI） is a pathological phenomenon that commonly occurs during liver surgery and transplantation. It leads to serious tissue damage and affects liver function. The mechanisms behind IRI are complex，involving oxidative stress，inflammatory responses，and calcium homeostasis disorder. Recently，scientists have paid more attention to the role of endoplasmic reticulum stress（ERS） in IRI. ERS activates three classical signaling pathways，PERK，IRE1，and ATF6，through the unfolded protein response（UPR），aiming to preliminarily restore endoplasmic reticulum homeostasis and protect cells. However，if the stress response is excessive or persistent，ERS can activate apoptosis signaling pathways，such as CHOP and Bax/Bak，worsening cell injury. Additionally，ERS is closely related to other cellular stress responses，such as autophagy and oxidative stress，which jointly affect the survival and death of hepatocytes. Regulation of ERS，especially interventions targeting the three UPR pathways，is considered as a potential therapeutic pathway for alleviating hepatic IRI. Pharmacological interventions，such as 4-phenylbutyric acid and taurocholic acid，and gene therapies，such as knocking out PERK or IRE1，have shown positive effects in protecting liver function while inhibiting ERS. This paper reviews the mechanism of action of ERS in hepatic IRI，focuses on the specific roles of the three UPR pathways and their potential as therapeutic targets，and explores the future of related therapeutic strategies.
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