铁死亡在酒精性肝纤维化中的作用机制及其相关治疗策略

位志远; 林锋; 吴涛

doi:10.12449/JCH260525

铁死亡在酒精性肝纤维化中的作用机制及其相关治疗策略

DOI: 10.12449/JCH260525

海南医科大学附属海南医院/海南省人民医院感染科，海口 570311

基金项目:

国家自然科学基金 (82160303);

海南省重点研发项目 (ZDYF2021SHFZ050)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：位志远负责分析资料，查找文献，文章撰写；林锋负责修改文章；吴涛负责文章审阅，经费支持。

详细信息

通信作者:
吴涛， wutao1_ren@163.com （ORCID： 0000-0002-3887-645X）

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出版历程
- 收稿日期: 2026-02-09
- 录用日期: 2026-02-24
- 出版日期: 2026-05-20

Ferroptosis in alcoholic liver fibrosis： Mechanism of action and therapeutic strategies

Department of Infectious Diseases，Hainan Affiliated Hospital of Hainan Medical University/Hainan Provincial People’s Hospital，Haikou 570311，China

Research funding:

National Natural Science Foundation of China (82160303);

Key R&D Project in Hainan Province (ZDYF2021SHFZ050)

More Information

Corresponding author: WU Tao， wutao1_ren@163.com （ORCID： 0000-0002-3887-645X）

摘要

摘要: 酒精性肝纤维化是酒精性肝病进展为肝硬化的关键环节，目前缺乏疗效确切的特异性抗纤维化治疗策略。近年来研究发现，铁死亡（一种铁依赖性脂质过氧化的程序性细胞死亡）在酒精相关肝细胞损伤与纤维化进程中发挥重要作用。乙醇代谢产生的活性氧可损伤肝细胞并削弱其抗氧化防御能力，导致铁稳态失衡及脂质过氧化物蓄积，最终触发铁死亡。肝细胞铁死亡通过放大炎症反应及激活肝星状细胞，促进纤维化进展；而选择性诱导已活化的肝星状细胞发生铁死亡则可减轻纤维化，呈现“双刃剑”效应。现有铁死亡干预措施主要聚焦于抗氧化、降低铁负荷或阻断脂质过氧化放大等，初步显示出一定疗效和潜在临床价值，但仍存在作用单一、细胞选择性不足等局限性。未来有望通过纳米递送等手段，实现多通路协同和细胞特异性干预，进一步提升铁死亡调控策略的抗纤维化疗效。
- 肝疾病，酒精性 /
- 肝纤维化 /
- 铁死亡 /
- 过氧化脂质类
Abstract: Alcoholic liver fibrosis is a critical step in the progression of alcoholic liver disease toward liver cirrhosis， yet there is currently still a lack of effective and specific anti-fibrotic therapeutic strategies. Recent studies have shown that as an iron-dependent， lipid peroxidation-driven form of regulated cell death， ferroptosis plays an important role in alcohol-related hepatocellular injury and fibrogenesis. Reactive oxygen species generated during alcohol metabolism can damage hepatocytes， impair their antioxidant defense ability， and lead to disruption of iron homeostasis and accumulation of lipid peroxides， ultimately triggering ferroptosis. Hepatocyte ferroptosis can promote fibrosis by amplifying inflammatory responses and activating hepatic stellate cells， whereas selective induction of ferroptosis in activated hepatic stellate cells may attenuate fibrosis， highlighting the “double-edged sword” effect of ferroptosis. Current interventions against ferroptosis mainly focus on applying antioxidant approaches， reducing iron burden， or blocking the amplification of lipid peroxidation， which have shown preliminary efficacy and a potential clinical value， but there are still limitations such as single-target actions and insufficient cell selectivity. In the future， nanotechnology-based delivery and other targeting strategies may help to realize multi-pathway coordination and cell-specific modulation， thereby improving the anti-fibrotic efficacy of ferroptosis-oriented therapies.
- Liver Diseases， Alcoholic /
- Hepatic Fibrosis /
- Ferroptosis /
- Lipid Peroxides

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注： a，ROS驱动的铁稳态紊乱与游离铁池扩增及肠-肝轴相关调控；b，胱氨酸/谷氨酸逆向转运体-GSH-GPX4轴与脂质过氧化；c，蛋氨酸循环-转硫途径；d，Nrf2信号通路与抗氧化基因调控；e，肝细胞铁死亡介导无菌炎症并促进HSC活化与肝纤维化进展。ALF，酒精性肝纤维化；ROS，活性氧；SIRT1，沉默信息调节因子1；LCN2，脂质运载蛋白2；IRP1，铁调节蛋白1；IRE，铁反应元件；Tf，转铁蛋白；DMT1，二价金属转运体1；Fe²⁺，二价铁离子；Fe³⁺，三价铁离子；NCOA4，核受体共激活因子4；·OH，羟基自由基；NADP⁺，氧化型烟酰胺腺嘌呤二核苷酸磷酸；NADPH，还原型烟酰胺腺嘌呤二核苷酸磷酸；GCS，γ-谷氨酰半胱氨酸合成酶；GSS，谷胱甘肽合成酶；GSR，谷胱甘肽还原酶；GSSG，氧化型谷胱甘肽；GSH，还原型谷胱甘肽；GPX4，谷胱甘肽过氧化物酶4；Se，硒；PL-PUFA，含多不饱和脂肪酸的磷脂；PLOOH，磷脂氢过氧化物；PLOO·，磷脂过氧自由基；Keap1，Kelch样ECH相关蛋白1；Nrf2，核转录因子红系2相关因子2；Bach1，BTB与CNC同源蛋白1；Maf，Maf家族转录因子；ARE，抗氧化反应元件；DAMP，损伤相关分子模式；TLR4，Toll样受体4；NF-κB，核因子κB；P2X7，嘌呤能受体P2X7；NLRP3，核苷酸结合寡聚结构域样受体家族热蛋白结构域相关蛋白3；IL-1β，白细胞介素1β；TNF-α，肿瘤坏死因子α；IL-6，白细胞介素6；TGF-β，转化生长因子β；Smad，母系抗十五表态蛋白同源物；Fenton反应，芬顿反应。

图 1 ALF中铁死亡的分子机制与调控网络

Figure 1. Molecular mechanisms and signaling network of ferroptosis in alcoholic liver fibrosis

下载: 全尺寸图片幻灯片

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