引用本文
周鸣, 曾子键, 杨希坤, 李晖. 肝细胞程序性细胞死亡在肝纤维化中的作用[J]. 中华肝脏病杂志, 2026, 34(9):922-929. DOI: 10.3760/cma.j.cn501113-20250918-00393.
通信作者：
李晖，成都中医药大学附属医院中心实验室
摘要
肝纤维化是慢性肝病发生和发展的关键环节，抑制肝纤维化对慢性肝病的防治具有重要意义。随着对肝细胞研究的深入，研究者发现不同的诱因刺激肝细胞，会使肝细胞通过不同的分子机制，发生相应的程序性细胞死亡（包括细胞凋亡、坏死性凋亡、焦亡、泛凋亡、铁死亡、铜死亡和自噬），进而对肝纤维化造成促进或抑制的作用。通过调控肝细胞程序性细胞死亡，可缓解或加剧纤维化进展。现阐述不同肝细胞程序性细胞死亡在肝纤维化中的作用、诱发肝细胞程序性细胞死亡的相关机制，以及通过干预肝细胞程序性细胞死亡以调控肝纤维化的相关措施，以期为肝纤维化防治提供新的理论依据。
正文
肝细胞、肝巨噬细胞、肝窦内皮细胞和肝星状细胞（hepatic stellate cell，HSC）是肝纤维发生机制中的4种核心细胞，它们组成了肝纤维化过程中各个环节的关键枢纽，联合管理纤维化机制［1］。程序性细胞死亡（programmed cell death，PCD）是维持机体内在平衡的重要机制，在机体的组织细胞内广泛存在，目前发现的PCD形式包括细胞凋亡、坏死性凋亡、焦亡、泛凋亡、铁死亡、铜死亡和自噬。
肝纤维化的发病过程中涉及多种细胞的PCD、同种细胞的不同PCD以及不同PCD之间的串扰，它们对纤维化进展发挥着双向作用：消除促纤维化细胞，如活化HSC和M1型巨噬细胞的PCD，能减缓肝纤维化进展；损伤维持肝脏正常生理功能的基础细胞如肝细胞、肝窦内皮细胞和M2型巨噬细胞的PCD，则会加剧肝纤维化的发生和发展［2］。肝细胞是肝损伤后发生PCD的主体细胞和肝纤维化的始动因素，它的PCD形式往往决定后续的肝纤维化发生和发展机制。研究结果显示，肝细胞PCD由基因调节，会对肝纤维化造成双重影响，调控肝细胞PCD机制可缓解或加剧纤维化进展［3］。因此，调控肝细胞PCD可能是防治肝纤维化的有效措施。本文基于肝细胞的不同PCD形式，对肝细胞PCD对肝纤维化的作用、诱导肝细胞PCD的相关机制及通过干预肝细胞PCD以调控肝纤维化的相关措施进行综述。
一、
肝细胞凋亡
过度的肝细胞凋亡则会促进肝纤维化的发生和发展。各种肝病诱因上调肝细胞内促凋亡蛋白与抑凋亡蛋白的比值，会促使肝细胞凋亡，凋亡肝细胞会释放凋亡小体（apoptotic body，AB），AB被HSC和巨噬细胞吞噬可诱导促纤维化反应［4］。因此，阻止肝细胞凋亡或许能抑制促纤维化反应，延缓肝纤维化进展。
肝细胞凋亡受到复杂且多样化的分子调控网络影响，包括特定基因、非编码RNA、信号蛋白及激素等在内的多种因子，均可通过调节肝细胞凋亡的平衡，深刻影响肝纤维化的发生与发展。在四氯化碳肝纤维化小鼠体内及原代肝细胞体外实验中，铁调素可通过抑制蛋白激酶R样内质网激酶通路促使B细胞淋巴瘤/白血病-2（B-cell lymphoma/leukemia-2，Bcl-2）蛋白表达升高、其相关X蛋白（Bax）表达降低，阻止肝细胞凋亡并改善肝纤维化［5］。通过代谢相关脂肪性肝炎（metabolic associated steatohepatitis，MASH）小鼠体内实验及肝细胞体外实验结果显示，上调新型抗凋亡信号（CD1d-JAK2-STAT3）轴可增加Bcl-xL和Mcl-1的表达，同时减少胱天蛋白酶（caspase）-3/7的表达，进而抑制肝细胞凋亡，防止MASH进一步恶化［6］。通过体内外研究证明，缺氧相关因子（hypoxia-associated factor，HAF）可上调肿瘤坏死因子受体相关死亡结构域蛋白（TNFRSF1A-associa-ted via death domain，TRADD）和受体相互作用蛋白激酶（receptor-interacting protein kinase，RIPK）1的转录，激活核因子（nuclear factor，NF）-κB通路增加磷酸化NF-κB p65亚基（P-p65）和p50亚基（P-p50）的表达，抑制肝细胞凋亡，改善MASH预防其进展为HCC［7］。 PNPLA3基因的I148M变体表达可导致肝脏脂质积累，使肝细胞发生脂毒性凋亡，产生AB和损伤相关分子模式（damage associated molecular pattern，DAMP），诱导巨噬细胞M1型极化和HSC活化，促进肝纤维化进展［8］。Wang等［9］发现成纤维细胞生长因子4可磷酸化肝细胞中的雌激素相关受体γ，促使其泛素化降解，避免乙醇刺激雌激素相关受体γ后，使细胞色素P450 2E1基因过表达，导致肝细胞凋亡增加及肝脏炎症和纤维化的发生。let-7 miRNA可通过甲基胞嘧啶双加氧酶3siRNA的负反馈回路减少肝细胞中转化生长因子β1的产生，也可经转录后直接抑制Fas表达，进而抑制两种死亡因子介导的肝细胞凋亡，减轻胆管结扎诱导的肝纤维化［10］。研究结果显示，敲低趋化因子（C-X-C基元）配体1可减弱小鼠肝脏中性粒细胞的浸润，降低炎性细胞因子的表达，并显著下调活性氧（reactive oxygen species，ROS）的产生和caspase-3相关肝细胞凋亡，从而改善慢加急性肝衰竭的肝损伤［11］。过度训练产生的乳酸体会促进髓系细胞白血病序列1基因表达，相关蛋白可上调促凋亡基因 BAX和 BAK的表达，进而诱导肝细胞凋亡释放AB，使HSC活化［12］。经乙型肝炎相关慢加急性肝衰竭患者前瞻性多中心队列研究结合肝细胞体外实验结果显示，信号蛋白-6B（SEMA6B）在肝细胞中过表达可通过停滞G
0
/G
1
细胞周期抑制肝细胞增殖并诱导细胞凋亡，上调炎症相关通路，加剧肝功能衰竭［13］。
除上述调控肝细胞凋亡的机制性研究外，部分天然化合物和益生菌也被发现可通过干预上述机制，抑制肝细胞凋亡，改善不同病因引起的肝纤维化。橙皮苷可通过恢复血管内皮生长因子A-磷酸肌醇3-激酶（phosphoinositide 3-kinase，PI3K）/蛋白酶B（AKT）信号通路的传导抑制肝细胞凋亡，缓解代谢相关脂肪性肝病（metabolic associated fatty liver disease，MAFLD）［14］。桧木酮可通过上调法尼醇-X受体及其下游靶基因 SHP和 CES1的表达，减弱肝细胞脂质沉积并降低caspase-8水平，从而抑制肝细胞凋亡，减轻MASH纤维化［15］。副干酪乳杆菌HY7207能下调Bax/Bcl-2蛋白的比值，抑制HepG2细胞凋亡；还能下调 Srebp1c等脂肪生成基因、Tnf等炎症基因和 Col1a1等纤维化基因的表达，改善MAFLD小鼠的肝脏脂肪堆积、炎症和纤维化［16］。
二、
肝细胞坏死性凋亡
肝细胞坏死性凋亡具有促纤维化作用，抑制肝细胞坏死性凋亡是治疗肝纤维化的新途径。当凋亡相关因子受体被激活但caspase-8缺乏的情况下，去泛素化酶柱状素会激活RIPK1，RIPK1通过与RIPK3相互作用，募集并激活混合谱系激酶结构域样蛋白（mixed lineage kinase domain-like protein，MLKL），进而诱导肝细胞坏死性凋亡释放DAMP，诱发肝脏炎症并激活HSC，促进肝纤维化进展［2］。
经多种动物及细胞实验证明，肝细胞坏死性凋亡的核心分子通路RIPK3/MLKL是肝脏受多种病理刺激如肥胖、胆汁淤积、缺氧及乙醇等后，驱动肝纤维化发生和发展的重要途径。Selvarani等［17］研究结果显示，RIPK3和MLKL高表达所诱导的肝细胞坏死性凋亡，会使肥胖小鼠肝脂肪变性进展为肝纤维化和肝细胞腺瘤的概率显著增加，而下调肝细胞MLKL蛋白的表达，可显著减轻四氯化碳诱导的肝纤维化；进一步的研究显示，MLKL缺失可通过减少肝细胞坏死性凋亡，抑制HSC激活来阻断肝纤维化。肝细胞受胆汁酸刺激可释放JNK/c-Jun信号上调C-C基序趋化因子配体2和3的表达，进而促进CD14
＋
和CD16
＋
型单核细胞浸润并分泌肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）和凋亡相关因子配体（FasL），两种死亡因子与RIPK1/RIPK3/MLKL轴相互作用可驱动肝细胞坏死性凋亡，加剧胆汁淤积性肝损伤［18］。缺氧引起的线粒体损伤和Z-DNA积累可导致肝细胞Z-DNA结合蛋白1（Z-DNA binding protein 1，ZBP1）/RIPK3依赖性坏死性凋亡，加重肝缺血再灌注损伤［19］。在酗酒诱发的慢加急性肝衰竭体内外模型实验中，乙醇可促进中性粒细胞浸润和胞外陷阱增加，进而触发肝细胞释放RIPK3诱导坏死性凋亡，加剧慢加急性肝衰竭［20］。
基于上述肝细胞坏死性凋亡诱导蛋白的研究结果显示，临床药物和强致癌物也可通过干预相关途径影响肝纤维化进展。二甲双胍可作用于肝细胞和肝巨噬细胞中的腺苷酸活化蛋白激酶（AMP-activated protein kinase，AMPK）-沉默信息调节因子1信号通路（Sirt1）通路，激活三甾四脯氨酸，进而抑制肝巨噬细胞释放TNF-α，减少肝细胞坏死性凋亡，缓解MAFLD［21］。低剂量黄曲霉毒素B1可通过促进Toll样受体（Toll-like receptor，TLR）4介导肝细胞坏死性凋亡加重MASH［22］。四溴双酚S会抑制PINK1-PAKIN信号通路介导的线粒体自噬，导致THLE-2和AML12细胞中的受损线粒体积累，随后累积的ROS可促进RIPK3/MLKL的表达，诱导肝细胞坏死性凋亡，加剧肝脏炎症［23］。
三、
肝细胞焦亡
肝细胞焦亡导致的持续性炎症会促进肝纤维化发展，在肝纤维化过程中发挥关键作用。肝细胞内的核苷酸结合寡聚化结构域样受体蛋白3（NOD-like receptor thermal protein domain associated protein 3，NLRP3）炎性小体可诱导肝细胞焦亡，焦亡肝细胞所释放的炎性小体颗粒被HSC内化后，可诱导HSC活化，促进肝纤维化发展［24］。
在肝纤维化的进程中，NLRP3炎性小体介导的肝细胞焦亡是驱动肝脏炎症与纤维化的核心环节，其活性受到关键抑制性分子、核心促进分子、新发现的表观遗传学机制及其他分子调控机制等多层次分子网络的精密调控。关键抑制性分子，核受体亚家族5组A成员2上调醛脱氢酶1家族成员B1的表达，降低ROS水平，抑制NF-κB-NLRP3通路，减少肝细胞焦亡并缓解MASH［25］； NT5E编码的CD73蛋白可通过下调PI3K/AKT信号通路抑制NLRP3炎性小体介导的肝细胞焦亡，减轻酒精性脂肪性肝炎导致的肝损伤［26］；G蛋白偶联受体56通过抑制NF-κB/NLRP3通路介导的肝细胞焦亡，可减少HSC活化，缓解肝纤维化进展［27］；生长停滞特异性5分子可通过调节miR-684-AHR轴抑制肝细胞焦亡和HSC激活，阻止肝纤维化进一步发展［28］。核心促进分子，胞苷/尿苷单磷酸激酶2和高尿酸均可诱导NLRP3/人D蛋白（gasdermin D，GSDMD）通路介导的肝细胞焦亡，促进MAFLD进展为MASH；进一步的干预试验结果显示，通过基因调控或给予去甲二氢愈创木酸药物抑制胞苷/尿苷单磷酸激酶2活化，可影响后续通路，减少肝细胞焦亡，缓解肝脏炎症和纤维化［29,30］。新发现的表观遗传学机制表明，甲基转移酶样3（methyltransferase-like 3，METTL3）可分别通过与Discs大同源物关联蛋白5结合或与蛋白磷酸酶2A相互作用，激活NF-κB/NLRP3信号通路促进肝细胞焦亡，驱动肝巨噬细胞代谢重编程和M1型极化，加剧MASH纤维化；而使用METTL3的靶向抑制剂STM2457可显著减轻HBx-Tg小鼠NLRP3依赖性MASH［31,32］；活化的干扰素基因刺激因子（stimulator of interferon genes，STING）-WDR5/DOT1L/IRF3-NLRP3信号通路可诱导肝细胞焦亡，增强肝脏炎症促进肝纤维化进展［33］。其他分子调控机制，硒蛋白W可通过调节代谢重编程来激活巨噬细胞的cGAS/STING信号传导，从而促进肝细胞焦亡，加剧MAFLD的进展［34］。在脂毒性AML12和原代小鼠肝细胞体外模型中，敲低含溴结构域蛋白4可抑制NLRP3/GSDMD通路介导的肝细胞焦亡，缓解MASH的进展［35］。免疫层面，PD-1
＋
CD8
＋
T细胞可通过增加颗粒酶B和穿孔素1的产生诱导肝细胞焦亡，加剧自身免疫性肝病的炎症进展［36］。
基于上述NLRP3炎性小体的核心调控机制研究，靶向抑制其介导的肝细胞焦亡已成为开发抗肝纤维化治疗策略的重要方向，其中多种天然化合物在动物和细胞实验中展现出显著潜力。龙胆苦苷、低聚原花青素、特女贞子苷及鸦胆子素A等中药单体可分别通过下调TLR4、减少组织蛋白酶B泄漏并下调ROS-MLKL-织蛋白酶B信号通路、上调沉默调节蛋白6抑制嘌呤受体P2X7表达、阻断肝细胞内的核受体亚家族2组F成员2-高迁移率族蛋白B1炎症信号级联通路来抑制NLRP3激活诱导的肝细胞焦亡，进而抑制HSC活化、巨噬细胞M1型极化及白细胞介素-1β和白细胞介素-18诱导的炎症扩散，从而分别改善MASH、酒精相关性肝病（alcohol-associated liver disease，ALD）型肝纤维化［37,38,39,40］。中药复方“益气健脾方”也被证实可下调NLRP3/caspase-1/GSDMD信号通路或通过调节三羧酸循环恢复线粒体功能，抑制肝细胞焦亡，改善肝脏炎症和纤维化［41］。
四、
肝细胞泛凋亡
细胞凋亡、坏死性凋亡、细胞焦亡通过泛凋亡机形成动态分子网络，泛凋亡既有三者的主要特征，也有自己独特的调控机制，如ZBP1和黑素瘤缺乏因子2（absent in melanoma 2，AIM2）便是合成泛凋亡复合物的关键启动分子，在特定条件下可主导完成泛凋亡复合物的组装，进而通过激活caspase-1、caspase-8和RIPK3，启动三条程序性细胞死亡通路诱导细胞泛凋亡。肝细胞泛凋亡是多种慢性肝病的刺激因素，如可促进MASH的发展，导致炎症性纤维化和肝细胞死亡［42］。
ZBP1和AIM2诱导的细胞泛凋亡在多种诱导肝纤维化的病理损伤如ALD、MAFLD、肝缺血再灌注损伤及药物性肝损伤中广泛存在，受多种细胞因子调控，主要以诱导肝细胞死亡的形式，促进肝纤维化进展。经纤维连接蛋白Ⅲ型结构域包含蛋白4处理的HepG2细胞，被TNF-α刺激后的肝细胞泛凋亡减弱，MAFLD炎症及纤维化缓解［43］。而STING可通过感知线粒体DNA的释放，诱导肝细胞泛凋亡，加重肝缺血再灌注损伤［44］。Zeng等［45］研究结果显示，敲低AIM2基因能减少肝细胞泛凋亡，从而显著减轻对乙酰氨基酚过量所诱导的药物性肝损伤；反之，利用腺相关病毒9恢复AIM2表达则会增加泛凋亡，加重肝损伤；此外，过量对乙酰氨基酚会导致人原代肝细胞泄漏线粒体DNA，进而通过激活TLR9通路促进中性粒细胞胞外陷阱形成，诱导肝细胞泛凋亡；而预注射脱氧核糖核酸酶Ⅰ可有效缓解该过程引发的药物性肝损伤。
基于上述泛凋亡机制，给予MAFLD肝细胞模型铁死亡抑制剂利普司他汀-1可防止其在脂质应激下由促泛凋亡分子如TNF-α，脂多糖和nigericin等诱导出现泛凋亡；利普司他汀-1明显降低了MAFLD小鼠模型ROS的含量和肝纤维化相关分子的表达［46］。这证明了抑制肝细胞泛凋亡可缓解肝纤维化进展，也说明铁死亡与泛凋亡之间可能存在潜在联系。此外，急性肝衰竭与法尼基转移酶的表达呈正相关，而法尼基转移酶的抑制剂PD083176可通过减少肝细胞泛凋亡，显著减轻急性肝衰竭小鼠的肝损伤［47］。法尼基转移酶可能是肝细胞泛凋亡的正向调节因子。中医药领域研究结果也显示，四物汤可通过抑制小鼠原代肝细胞泛凋亡，阻断巨噬细胞M1型极化和HSC活化，改善MAFLD纤维化［48］。
五、
肝细胞铁死亡和铜死亡
在抗脂质过氧化体系如谷胱甘肽过氧化物酶4（glutath-ione peroxidase 4，GPX4）失效的前提下，铁积累可通过芬顿反应诱导细胞内脂质过氧化物积累，引起细胞铁死亡。目前细胞铁死亡与肝纤维化的相关性研究主要集中在肝细胞。研究结果表明，肝细胞铁死亡是促纤维化机制的核心之一，抑制肝细胞铁死亡可以改善肝纤维化［49］。
多个独立研究从不同分子途径共同揭示，肝细胞铁死亡是促进肝纤维化发生和发展的核心枢纽。在肝纤维化小鼠模型中，肝细胞特异性敲除转化生长因子激酶1会促进肝细胞铁死亡，因此衍生的氧化DNA损伤将激活STING信号，诱导M1型巨噬细胞极化；此外，肝细胞铁死亡也会促进DAMP，诱导HSC活化，加重肝纤维化［50］。另有研究结果显示，睾酮缺乏可通过靶向基本的螺旋-环-螺旋ARNT样蛋白1下调昼夜节律蛋白，诱导小鼠肝细胞铁死亡，从而加重高脂饮食诱导的MAFLD［51］。FUN14结构域包含蛋白1是一种线粒体自噬受体，通过96～133氨基酸结构域可与GPX4相互作用，促使GPX4从细胞质募集到线粒体中自噬降解，导致肝细胞铁死亡，其缺失可改善四氯化碳诱导小鼠的肝纤维化［52］。
另一方面，大量研究揭示了通过细胞疗法、菌类代谢物、激素及许多天然化合物干预肝细胞铁死亡的调控机制，从而改善慢性肝病的广阔前景。肝移植物中的人骨髓间充质干细胞可通过外泌体将miR-16-5p递送至肝细胞中，并在转录后抑制溶质载体家族3成员14依赖性肝细胞铁死亡，减轻肝脏缺血再灌注损伤［53］。毛螺菌代谢物可通过提高N-乙酰谷氨酸水平并通过kelch样ECH关联蛋白1泛素化降解及核因子-E2相关因子2（nuclear factor erythroid-2-related factor 2，NRF2）途径抑制肝细胞铁死亡来缓解ALD［54］。外源性褪黑激素可通过褪黑素受体2-环磷酸腺苷-蛋白激酶A-肌醇需求酶1（MT2/cAMP/PKA/IRE1）信号通路抑制内质网应激，减少肝细胞铁死亡，改善MAFLD［55］。毛蕊花糖苷通过靶向多聚（rC）结合蛋白2基因，而丹参酸B通过上调细胞外基质蛋白1基因表达，均能抑制肝细胞铁死亡，分别改善肝缺血再灌注损伤与肝纤维化［56,57］。山奈酚、连翘苷-A、桧木醇及桃红四物汤内的苦杏仁苷、羟基藏红花黄A和芍药苷等中药单体均可通过上调NRF2-GPX4轴来抑制肝细胞铁死亡，从而分别在对乙酰氨基酚诱导肝损伤、胆管结扎诱导肝纤维化以及肝纤维化模型中发挥保护作用［58,59,60,61］。总桑黄菌提取物除可上调肝细胞内NRF2-GPX4通路抑制肝细胞铁死亡外，还能在肝纤维化小鼠体内下调转化生长因子-β1/Smad蛋白信号转导通路以抑制HSC活化，改善肝纤维化［62］。二聚胍内酯倍半萜类化合物则可通过减少肝细胞内的细胞衰老相关蛋白1介导的脂质积累与铁死亡，来改善肝脂肪变性［63］。
铜死亡是由于细胞内过度聚积的铜离子与三羧酸循环中的脂酰化成分直接结合，导致脂酰化蛋白聚集和铁硫簇蛋白不稳定，从而引发细胞死亡。Mao等［64］分析过往研究结果认为，肝脏中过量的铜积累会损害肝细胞并激活HSC，加速肝纤维化进展，靶向铜代谢可能是治疗肝纤维化的可行策略。已有研究结果证明，敲除铁氧还蛋白1可保护人HepaRG细胞免受对乙酰氨基酚的攻击，其机制与铜死亡相关；对小鼠的铁氧还蛋白1基因进行敲除，也改善了乙酰氨基酚诱导的肝损伤［65］。然而，关于肝细胞铜死亡在肝纤维化中的诱发机制，目前缺乏系统性研究；且铜积累对肝脏的损伤也待开展多种动物模型实验验证，并进一步分析其对具体细胞的影响和相关机制。
六、
肝细胞自噬
正常肝细胞自噬会产生存活信号，维持肝细胞的正常生理功能和结构，发挥保护肝脏、缓解肝纤维化的作用［66］，而过度的自噬则会导致肝细胞发生其他形式的PCD，促进肝纤维化进展。
多项研究表明，维持正常的肝细胞自噬活性是肝脏保护的关键。在ALD中，抑制内质网应激传感器X框结合蛋白1可恢复被乙醇抑制的溶酶体功能和自噬活性，进而减少肝细胞凋亡，改善纤维化［67］。肝细胞来源的血浆糖蛋白Fetuin-A可通过抑制TLR介导的自噬-溶酶体降解和肝巨噬细胞M2型极化，加剧ALD进展［68］。在MASH中，TNF-α/Miz1正反馈环可抑制肝细胞线粒体自噬加剧肝纤维化［69］。在HepG2和L02肝细胞体外模型中，TLR4通路可上调膜联蛋白A2的表达，减少AMPK/雷帕霉素靶蛋白（mTOR）介导的自噬通量促进脂质积累和MASH肝损伤［70］。此外，巨噬细胞通过STING-YAP轴可激活AMPK并诱导肝细胞发生脂噬，通过促进脂滴相关蛋白降解来控制MAFLD进展［71］。3-羟基-3-甲基戊二酰辅酶A还原酶降解蛋白1通过介导组蛋白去乙酰化酶2的降解，可上调过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR）-α介导的肝细胞自噬，改善单纯缺氧诱导的MAFLD［72］。
相反，在某些病理条件下，过度或选择性的肝细胞自噬会加剧肝损伤，促进肝纤维化。例如，慢性间歇性缺氧会触发肝细胞选择性自噬，降解DNA修复酶Eepd1，从而加剧DNA损伤并上调促纤维化基因表达［73］。甲基胞嘧啶双加氧酶3通过促进ENPP1的低甲基化来增强肝细胞自噬，从而恶化MAFLD，使肝纤维化持续存在［74］。
研究结果显示，可促进肝细胞自噬的临床药物和天然化合物大多起抑制肝纤维化的作用。Shen等［75］研究结果显示，许多可激活和恢复肝细胞自噬的药物能促进肝细胞中的脂滴清除、抑制促炎因子产生和HSC活化，改善肝纤维化，减缓MAFLD的进展。非诺贝特可诱导溶酶体Ca
2+
通过肝细胞内的黏磷脂1释放，激活钙调神经磷酸酶和钙调蛋白依赖性蛋白激酶激酶β-AMPK-Unc-51样激酶（ULK1）通路，促进转录因子EB和转录因子E3去磷酸化和核易位，增强肝细胞自噬，改善MAFLD纤维化［76］。阿培利司和地高辛可通过激活肝细胞自噬，减少肝脏内脂质积累，减轻MASH的炎症和纤维化［77］。武替拉布利定（vutiglabridin）是一种新开发的抗肥胖候选药，体外研究结果显示，vutiglabridin治疗可促进L02细胞系的脂质分解、自噬和线粒体功能改善，显著减少肝脂肪变性、纤维化和炎症［78］。千层纸苷可通过影响PPAR-α同源受体PPAR-γ调节AMPK-ULK1途径，启动肝细胞自噬，减少氧化应激、DNA损伤和炎症细胞因子白细胞介素-6的产生，抑制HSC活化和纤维化进展［79］。
然而也有少部分药物会引起肝细胞过度自噬导致肝细胞死亡，加重肝纤维化。如吉特替尼会导致药物性肝损伤加剧肝纤维化；靶向抑制自噬途径是减轻吉特替尼诱导的肝毒性的潜在治疗策略［80］。
七、
总结与展望
基于上述研究可知，肝细胞凋亡、坏死性凋亡、焦亡、铁死亡、铜死亡、泛凋亡和病理性肝细胞自噬会促进肝纤维化进展，而维持正常的肝细胞自噬活性则可以抑制肝纤维化进展。虽然诱发肝细胞各PCD形式的关键分子和各肝细胞PCD对肝纤维化的作用已初步明确（ 图1 ），但肝细胞PCD发生后的下游信号分子通路与肝巨噬细胞、肝窦内皮细胞和HSC发生相互作用，进一步引发肝纤维化的细胞和分子机制研究仍然匮乏，有待进一步探索，为肝纤维化的防治提供更多的理论依据。此外，目前开展的实验性研究并未指明不同病因诱导的肝纤维化是否具有激活特异肝细胞PCD通路的倾向性，这方面仍待开展动物及人肝组织模型实验进一步验证；不同病因诱导的肝纤维化中主要涉及的肝细胞PCD形式见 表1 。
临床转化方面，肝细胞PCD过程中释放的特异性分子或可作为新型生物标志物用于肝纤维化的早期诊断与预后评估；而靶向肝纤维化相关机制的促进或抑制分子，可能成为新型抗肝纤维化靶向药物研发的突破口；部分药物的药理学机制也有待进一步开展实验验证，或许其未开发的药理作用能使其成为新的临床抗肝纤维化候选药物；此外，许多天然化合物及中药复方已被证实，可通过调控肝细胞PCD途径改善肝纤维化，因而中医药在肝纤维化防治方面是一个巨大的宝库，有待进一步发掘。
参考文献
[1]Kisseleva T ,Brenner D . Molecular and cellular mechanisms of liver fibrosis and its regression[J]. Nat Rev Gastroenterol Hepatol, 2021,18(3):151-166. DOI: 10.1038/s41575-020-003-72-7 .
[2]Gao R ,Tang H ,Mao J . Programmed cell death in liver fibrosis[J]. J Inflamm Res, 2023,16:3897-3910. DOI: 10.2147/JIR.S427868 .
[3]Lu JL ,Yu CX ,Song LJ . Programmed cell death in hepatic fibrosis:current and perspectives[J]. Cell Death Discov, 2023,9(1):449. DOI: 10.1038/s41420-023-01749-8 .
[4]Roehlen N ,Crouchet E ,Baumert TF . Liver fibrosis: mechanistic concepts and therapeutic perspectives[J]. Cells, 2020,9(4):875. DOI: 10.3390/cells9040875 .
[5]Li C ,Pang G ,Zhao W ,et al. Hepcidin inhibits hepatocyte apoptosis through the PERK pathway in acute liver injury and fibrosis[J]. Hepatol Commun, 2024,9(1):e0604. DOI: 10.1097/HC9.0000000000000604 .
[6]Lei Z ,Yu J ,Wu Y ,et al. CD1d protects against hepatocyte apoptosis in non-alcoholic steatohepatitis[J]. J Hepatol, 2024,80(2):194-208. DOI: 10.1016/j.jhep.2023.10.025 .
[7]Acuña-Pilarte K ,Reichert EC ,Green YS ,et al. HAF prevents hepatocyte apoptosis and progression to MASH and HCC through transcriptional regulation of the NF-κB pathway[J]. Hepatology, 2025,82(2):438-453. DOI: 10.1097/HEP.000000-0000001070 .
[8]CastanhoMartins M ,Dixon ED ,Lupo G ,et al. Role of PNPLA3 in hepatic stellate cells and hepatic cellular crosstalk[J]. Liver Int, 2025,45(4):e16117. DOI: 10.1111/liv.16117 .
[9]Wang L ,Dong W ,Fan L ,et al. Repression of the ERRγ-CYP2E1 pathway by FGF4 mitigates alcohol-associated liver injury[J]. Hepatology, 2025,82(5):1138-1154. DOI: 10.1097/HEP.000000-0000001282 .
[10]Song J ,Lv H ,Liu B ,et al. Let-7 suppresses liver fibrosis by inhibiting hepatocyte apoptosis and TGF-β production[J]. Mol Metab, 2023,78:101828. DOI: 10.1016/j.molmet.2023.101828 .
[11]Tang S ,Zhang J ,Zhang L ,et al. Knockdown of CXCL1 improves ACLF by reducing neutrophil recruitment to attenuate ROS production and hepatocyte apoptosis[J]. Hepatol Commun, 2023,7(10):e0257. DOI: 10.1097/HC9.0000000000000257 .
[12]Liu Y ,Zhou R ,Guo Y ,et al. Muscle-derived small extracellular vesicles induce liver fibrosis during overtraining[J]. Cell Metab, 2025,37(4):824-841.e8. DOI: 10.1016/j.cmet.2024.12.005 .
[13]Yang H ,Cai Q ,Xin J ,et al. SEMA6B induces macrophage-mediated inflammation and hepatocyte apoptosis in hepatitis B virus-related acute-on-chronic liver failure[J]. Theranostics, 2024,14(13):5200-5218. DOI: 10.7150/thno.97007 .
[14]Li A ,Nie T ,Wang X ,et al. Hesperidin ameliorates hepatocyte cell cycle disruption, apoptosis, and necroptosis in mice with nonalcoholic fatty liver disease via the VEGFA-PI3K/AKT pathway[J]. Int Immunopharmacol, 2025,163:115304. DOI: 10.1016/j.intimp.2025.115304 .
[15]Ma ZJ ,Qiu YK ,Yu ZW ,et al. Natural small molecule hinokitone mitigates NASH fibrosis by targeting regulation of FXR-mediated hepatocyte apoptosis[J]. J Adv Res, 2025,76:553-568. DOI: 10.1016/j.jare.2024.12.016 .
[16]Kim HJ ,Jeon HJ ,Kim DG ,et al. Lacticaseibacillus paracsei HY7207 alleviates hepatic steatosis, inflammation, and liver fibrosis in mice with non-alcoholic fatty liver disease [J]. Int J Mol Sci, 2024,25(18):9870. DOI: 10.3390/ijms25189870 .
[17]Selvarani R ,Nguyen HM ,Pazhanivel N ,et al. The role of inflammation induced by necroptosis in the development of fibrosis and liver cancer in novel knockin mouse models fed a western diet[J]. Geroscience, 2025,47(3):2973-2994. DOI: 10.1007/s11357-024-01418-3 .
[18]Zhu Z ,Xu Z ,Cao X ,et al. Conjugated bile acid-driven CD14 + CD16 + monocyte infiltration promotes cholestatic liver injury by enhancing hepatocyte necroptosis [J]. JHEP Rep, 2025,7(10):101517. DOI: 10.1016/j.jhepr.2025.101517 .
[19]Lin J ,Xu M ,Ji H ,et al. ZBP1-sensed hypoxic stress triggers intrinsic necroptosis in hepatocytes, aggravating hepatic ischemia-reperfusion injury:an experimental study[J]. Int J Surg, 2025,111(11):7761-7776. DOI: 10.1097/JS9.000000000-0003018 .
[20]Ortega-Ribera M ,Zhuang Y ,Babuta M ,et al. A novel multi-organ male model of alcohol-induced acute-on-chronic liver failure reveals NET-mediated hepatocellular death, which is prevented by RIPK3 inhibition[J]. Cell Mol Gastroenterol Hepatol, 2025,19(4):101446. DOI: 10.1016/j.jcmgh.2024.101446 .
[21]Park J ,Rah SY ,An HS ,et al. Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis[J]. Metabolism, 2023,141:155516. DOI: 10.1016/j.metabol.2023.155516 .
[22]Zeng J ,Chen L ,Tang J ,et al. Short-term exposure to low doses of aflatoxin B1 aggravates nonalcoholic steatohepatitis by TLR4-mediated necroptosis[J]. Free Radic Biol Med, 2025,226:129-142. DOI: 10.1016/j.freeradbiomed.2024.11.027 .
[23]Yin Y ,Huang M ,Xie J ,et al. TBBPS caused necroptosis and inflammation in hepatocytes by blocking PINK1-PARKIN-medi-ated mitochondrial autophagy[J]. Tissue Cell, 2024,88:102382. DOI: 10.1016/j.tice.2024.102382 .
[24]Zhang Y ,Zhangdi H ,Nie X ,et al. Exosomes derived from bmmscs mitigate the hepatic fibrosis via anti-pyroptosis pathway in a cirrhosis model[J]. Cells, 2022,11(24):4004. DOI: 10.3390/cells11244004 .
[25]Zhao R ,Guo Z ,Lu K ,et al. Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression[J]. Cell Death Dis, 2024,15(10):770. DOI: 10.1038/s41419-024-07151-1 .
[26]Zhu H ,Zhang M ,Ye Y ,et al. CD73 mitigates hepatic damage in alcoholic steatohepatitis by regulating PI3K/AKT-mediated hepatocyte pyroptosis[J]. Biochem Pharmacol, 2023,215:115753. DOI: 10.1016/j.bcp.2023.115753 .
[27]Shi Z ,Liu Q ,Zhang M ,et al. GPR56 function as a key repressor in hepatocyte pyroptosis and the pathogenesis of liver fibrosis. J Transl Med, 2025,23(1):632. DOI: 10.1186/s12967-025-06619-8 .
[28]Lang Z ,Zhang R ,Li X ,et al. GAS5-inhibited hepatocyte pyroptosis contributes to hepatic stellate cell inactivation via microRNA-684 and AHR[J]. iScience, 2023,26(8):107326. DOI: 10.1016/j.isci.2023.107326 .
[29]Zhu S ,Liao L ,Zhong Y ,et al. Hepatocellular CMPK2 promotes the development of metabolic dysfunction-associated steatohepatitis[J]. J Hepatol, 2025,83(2):383-396. DOI: 10.1016/j.jhep.2025.01.008 .
[30]Xu Z ,Tang C ,Song X ,et al. High uric acid exacerbates nonalcoholic steatohepatitis through NLRP3 inflammasome and gasdermin D-mediated pyroptosis[J]. J Biol Chem, 2025,301(6):110249. DOI: 10.1016/j.jbc.2025.110249
[31]Liu X ,Chen Z ,Lin J ,et al. DLGAP5 promotes acute liver injury via hepatocyte pyroptosis-driven macrophage metabolic reprogramming and M1 polarization[J]. Int J Biol Sci, 2025,21(12):5563-5585. DOI: 10.7150/ijbs.118024 .
[32]Du ZB ,Han T ,Cai YX ,et al. Hepatic steatosis and pyroptosis are induced by the hepatitis B virus X protein via B56α-METTL3 interaction-mediated m6A modification of the NLRP3 mRNA[J]. Cell Death Dis, 2025,16(1):698. DOI: 10.1038/s41419-025-08019-8 .
[33]Xiao Y ,Zhao C ,Tai Y ,et al. STING mediates hepatocyte pyroptosis in liver fibrosis by Epigenetically activating the NLRP3 inflammasome[J]. Redox Biol, 2023,62:102691. DOI: 10.1016/j.redox.2023.102691 .
[34]Miao Z ,Wang W ,Miao Z ,et al. Role of Selenoprotein W in participating in the progression of non-alcoholic fatty liver disease[J]. Redox Biol, 2024,71:103114. DOI: 10.1016/j.redox.2024.103114 .
[35]Chen F ,Li S ,Liu M ,et al. Targeting BRD4 mitigates hepatocellular lipotoxicity by suppressing the NLRP3 inflammasome activation and GSDMD-mediated hepatocyte pyroptosis[J]. Cell Mol Life Sci, 2024,81(1):295. DOI: 10.1007/s00018-024-05328-7 .
[36]Long J ,Yang SY ,Bian ZH ,et al. PD-1 + CD8 + T cell-mediated hepatocyte pyroptosis promotes progression of murine auto immune liver disease [J]. Adv Sci (Weinh), 2025,12(1):e2407284. DOI: 10.1002/advs.202407284 .
[37]Yong Q ,Huang C ,Chen B ,et al. Gentiopicroside improves NASH and liver fibrosis by suppressing TLR4 and NLRP3 signaling pathways[J]. Biomed Pharmacother, 2024,177:116952. DOI: 10.1016/j.biopha.2024.116952 .
[38]Jin Y ,Wang C ,Meng Z ,et al. Proanthocyanidins alleviate acute alcohol liver injury by inhibiting pyroptosis via inhibiting the ROS-MLKL-CTSB-NLRP3 pathway[J]. Phytomedicine, 2025,136:156268. DOI: 10.1016/j.phymed.2024.156268 .
[39]Qin BF ,Zhang JJ ,Feng QY ,et al. Specnuezhenide ameliorates hepatic fibrosis via regulating SIRT6-Mediated inflammatory signaling cascades[J]. J Ethnopharmacol, 2024,335:118646. DOI: 10.1016/j.jep.2024.118646 .
[40]Sun HM ,Feng QY ,Qin BF ,et al. Bruceine A attenuates fibrogenesis and inflammation through NR2F2-regulated HMGB1 inflammatory signaling cascades in hepatic fibrosis[J]. Eur J Pharmacol, 2025,987:177164. DOI: 10.1016/j.ejphar.2024.177164 .
[41]Zhao R ,Zhao Q ,Wang X ,et al. Yi-Qi-Jian-Pi formula inhibits hepatocyte pyroptosis through the IDH2-driven tricarboxylic acid cycle to reduce liver injury in acute-on-chronic liver failure[J]. J Ethnopharmacol, 2023,317:116683. DOI: 10.1016/j.jep.2023.116683 .
[42]Zhu P ,Ke ZR ,Chen JX ,et al. Advances in mechanism and regulation of PANoptosis:prospects in disease treatment[J]. Front Immunol, 2023,14:1120034. DOI: 10.3389/fimmu.2023.1120034 .
[43]Neira G ,Becerril S ,Valentí V ,et al. FNDC4 reduces hepatocyte inflammatory cell death via AMPKα in metabolic dysfunction-associated steatotic liver disease[J]. Clin Nutr, 2024,43(9):2221-2233. DOI: 10.1016/j.clnu.2024.08.007 .
[44]Wu C ,Miao H ,Yi Z ,et al. STING-mediated mitochondrial DNA release exacerbates PANoptosis in liver ischemia reperfusion injury[J]. Int Immunopharmacol, 2025,157:114778. DOI: 10.1016/j.intimp.2025.114778 .
[45]Zeng FL ,Zhang Y ,Wang ZH ,et al. Neutrophil extracellular traps promote acetamino phen-induced acute liver injury in mice via AIM2 [J]. Acta Pharmacol Sin, 2024,45(8):1660-1672. DOI: 10.1038/s41401-024-01239-2 .
[46]Tong J ,Lan XT ,Zhang Z ,et al. Ferroptosis inhibitor liproxstatin-1 alleviates metabolic dysfunction-associated fatty liver disease in mice:potential involvement of PANoptosis[J]. Acta Pharmacol Sin, 2023,44(5):1014-1028. DOI: 10.1038/s41401-022-01010-5 .
[47]Huang CL ,Qu HS ,Li AL ,et al. Design of a highly active peptide inhibitor of farnesyltransferase and its protective effect against acute liver failure[J]. Drug Des Devel Ther, 2025,19:1909-1926. DOI: 10.2147/DDDT.S505541 .
[48]Ma Z ,Xie K ,Xue X ,et al. Si-Wu-Tang attenuates hepatocyte PANoptosis and M1 polarization of macrophages in non-alcoholic fatty liver disease by influencing the intercellular transfer of mtDNA[J]. J Ethnopharmacol, 2024,328:118057. DOI: 10.1016/j.jep.2024.118057 .
[49]Yu Y ,Jiang L ,Wang H ,et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis[J]. Blood, 2020,136(6):726-739. DOI: 10.1182/blood.2019002907 .
[50]Su W ,Gao W ,Zhang R ,et al. TAK1 deficiency promotes liver injury and tumorigenesis via ferroptosis and macrophage cGAS-STING signalling[J]. JHEP Rep, 2023,5(5):100695. DOI: 10.1016/j.jhepr.2023.100695 .
[51]Fan Y ,Ren Y ,Deng L ,et al. Testosterone deficiency aggravates diet-induced non-alcoholic fatty liver disease by inducing hepatocyte ferroptosis via targeting BMAL1 in mice[J]. Int Immunopharmacol, 2025,144:113641. DOI: 10.1016/j.intimp.2024.113641 .
[52]Bi Y ,Liu S ,Qin X ,et al. FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner[J]. J Adv Res, 2024,55:45-60. DOI: 10.1016/j.jare.2023.02.012 .
[53]Deng Z ,Zeng W ,Gao Y ,et al. Mesenchymal stem cells prevent SLC39A14-dependent hepatocyte ferroptosis through exosomal miR-16-5p in liver graft[J]. Adv Sci (Weinh), 2025,12(6):e2411380. DOI: 10.1002/advs.202411380 .
[54]Zhang H ,Hu Q ,Zhang Y ,et al. Lachnospiraceae bacterium alleviates alcohol-associated liver disease by enhancing N-acetyl-glutamic acid levels and inhibiting ferroptosis through the KEAP1-NRF2 pathway[J]. Gut Microbes, 2025,17(1):2517821. DOI: 10.1080/19490976.2025.2517821 .
[55]Guan Q ,Wang Z ,Hu K ,et al. Melatonin ameliorates hepatic ferroptosis in NAFLD by inhibiting ER stress via the MT2/cAMP/PKA/IRE1 signaling pathway[J]. Int J Biol Sci, 2023,19(12):3937-3950. DOI: 10.7150/ijbs.85883 .
[56]Jia K ,Zhang Y ,Li F ,et al. Acteoside ameliorates h epatocyte ferroptosis and hepatic ischemia-reperfusion injury via targeting PCBP2 [J]. Acta Pharm Sin B, 2025,15(4):2077-2094. DOI: 10.1016/j.apsb.2025.03.002 .
[57]Fu Y ,Zhou X ,Wang L ,et al. Salvianolic acid B attenuates liver fibrosis by targeting Ecm1 and inhibiting hepatocyte ferroptosis[J]. Redox Biol, 2024,69:103029. DOI: 10.1016/j.redox.2024.103029 .
[58]Li H ,Weng Q ,Gong S ,et al. Kaempferol prevents acetaminophen-induced liver injury by suppressing hepatocyte ferroptosis via Nrf2 pathway activation[J]. Food Funct, 2023,14(4):1884-1896. DOI: 10.1039/d2fo02716j .
[59]Guo Q ,Wu Z ,Wang K ,et al. Forsythiaside-A improved bile-duct-ligation-induced liver fibrosis in mice: the involvement of alleviating mitochondrial damage and ferroptosis in hepatocytes via activating Nrf2[J]. Free Radic Biol Med, 2024,222:27-40. DOI: 10.1016/j.freeradbiomed.2024.05.042 .
[60]Yin X ,Liu Z ,Li C ,et al. Hinokitiol ameliorates MASH in mice by therapeutic targeting of hepatic Nrf2 and inhibiting hepatocyte ferroptosis[J]. Phytomedicine, 2025,139:156472. DOI: 10.1016/j.phymed.2025.156472 .
[61]Xiao Z ,Gao S ,Li S ,et al. Taohong Siwu Decoction modulates glutathione metabolism to suppress hepatocyte ferroptosis and demonstrates anti-fibrotic effects in the liver[J]. J Ethnopharmacol, 2025,350:120025. DOI: 10.1016/j.jep.2025.120025 .
[62]Gao S ,Wang X ,Xu Q ,et al. Total Sanghuangporus vaninii extract inhibits hepatocyte ferroptosis and intestinal microbiota disturbance to attenuate liver fibrosis in mice[J]. J Ethnopharma-col, 2025,345:119571. DOI: 10.1016/j.jep.2025.119571 .
[63]Liu Y ,Zhou F ,Zhao H ,et al. Dimeric guaianolide sesquiterpenoids from the flowers of Chrysanthemum indicum ameliorate hepatic steatosis through mitigating SIRT1-mediated lipid accumulation and ferroptosis[J]. J Adv Res, 2025,76:345-370. DOI: 10.1016/j.jare.2024.12.047 .
[64]Mao Y ,Chen H ,Zhu W ,et al. Cuproptosis cell death molecular events and pathways to liver disease[J]. J Inflamm Res, 2025,18:883-894. DOI: 10.2147/JIR.S498340 .
[65]Liu Y ,Yang Y ,Peng B ,et al. Targeting cuproptosis by FDX1 in acetaminophen-induced liver injury[J]. Chem Biol Interact, 2025,421:111753. DOI: 10.1016/j.cbi.2025.111753 .
[66]Allaire M ,Rautou PE ,Codogno P ,et al. Autophagy in liver diseases: time for translation?[J]. J Hepatol, 2019,70(5):985-998. DOI: 10.1016/j.jhep.2019.01.026 .
[67]Cheng Y ,Rao P ,Li S ,et al. Alcohol promotes hepatocyte injury via ER stress sensor XBP 1s mediated regulation of autophagy and lysosomal activity [J]. Toxicol Ap pl Pharmacol , 2024,492:117117. DOI: 10.1016/j.taap.2024.117117 .
[68]Lu S ,Jin H ,Nong T ,et al. Hepatocyte-derived Fetuin-A promotes alcohol-associated liver disease in mice by inhibiting autophagy-lysosome degradation of TLR and M2 macrophage polarization[J]. Free Radic Biol Med, 2024,224:506-520. DOI: 10.1016/j.freeradbiomed.2024.09.011 .
[69]Jin K ,Shi Y ,Zhang H ,et al. A TNFα/Miz1-positive feedback loop inhibits mitophagy in hepatocytes and propagates non-alcoh-olic steatohepatitis[J]. J Hepatol, 2023,79(2):403-416. DOI: 10.1016/j.jhep.2023.03.039 .
[70]Wu H ,Zhou M ,Jin Q ,et al. The upregulation of Annexin A2 by TLR4 pathway facilitates lipid accumulation and liver injury via blocking AMPK/mTOR-mediated autophagy flux during the development of non-alcoholic fatty liver disease[J]. Hepatol Int, 2024,18(4):1144-1157. DOI: 10.1007/s12072-023-10622-w .
[71]Yang T ,Qu X ,Wang X ,et al. The macrophage STING-YAP axis controls hepatic steatosis by promoting the autophagic degradation of lipid droplets[J]. Hepatology, 2024,80(5):1169-1183. DOI: 10.1097/HEP.0000000000000638 .
[72]Wang Y ,Chen Y ,Xiao X ,et al. HRD1-mediated ubiquitination of HDAC2 regulates PPARα-mediated autophagy and alleviates metabolic-associated fatty liver disease[J]. Biochim Biophys Acta Mol Cell Res, 2024,1871(7):119765. DOI: 10.1016/j.bbamcr.2024.119765 .
[73]Xiong J ,Xu Y ,Wang N ,et al. Obstructive sleep apnea syndrome exacerbates NASH progression via selective autophagy-mediated eepd1 degradation[J]. Adv Sci (Weinh), 2024,11(35):e2405955. DOI: 10.1002/advs.202405955 .
[74]Sun F ,Yang Y ,Jia L ,et al. TET3 boosts hepatocyte autophagy and impairs non-alcoholic fatty liver disease by increasing ENPP1 promoter hypomethylation[J]. Free Radic Biol Med, 2024,218:166-177. DOI: 10.1016/j.freeradbiomed.2024.04.207 .
[75]Shen Q ,Yang M ,Wang S ,et al. The pivotal role of dysregulated autophagy in the progression of non-alcoholic fatty liver disease[J]. Front Endocrinol (Lausanne), 2024,15:1374644. DOI: 10.3389/fendo.2024.1374644 .
[76]Yoo J ,Jeong IK ,Ahn KJ ,et al. Fenofibrate, a PPARα agonist, reduces hepatic fat accumulation through the upregulation of TFEB-mediated lipophagy[J]. Metabolism, 2021,120:154798. DOI: 10.1016/j.metabol.2021.154798 .
[77]Minami Y ,Hoshino A ,Higuchi Y ,et al. Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion[J]. Nat Commun, 2023,14(1):4084. DOI: 10.1038/s41467-023-39404-6 .
[78]Shin GC ,Lee HM ,Kim N ,et al. Paraoxonase-2 agonist vutiglabridin promotes auto phagy activation and mitochondrial function to alleviate non-alcoholic steatohepatitis [J]. Br J Pharmacol, 2024,181(19):3717-3742. DOI: 10.1111/bph.16438 .
[79]Liu Y ,Chen L ,Liu X ,et al. Oroxyloside inhibits liver fibrosis and hepatocarcinogenesis dependent on hepatocyte-specific knockout of Atg5[J]. Phytomedicine, 2025,145:157053. DOI: 10.1016/j.phymed.2025.157053 .
[80]Cao Y ,Chen Z ,Yin Y ,et al. Autophagy-dependent hepatocyte apoptosis mediates gilteritinib-induced hepatotoxicity[J]. Toxicol Lett, 2025,410:189-196. DOI: 10.1016/j.toxlet.2025.06.018 .
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