Caspase-3调控非酒精性脂肪性肝病细胞焦亡和凋亡的研究进展

Research progress in the role of caspase-3 in regulating pyroptosis and apoptosis in non-alcoholic fatty liver disease

摘要

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)是全球肝病的主要原因，包括非酒精性脂肪肝(non-alcoholic fatty liver，NAFL)、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis，NASH)和晚期纤维化，可导致肝硬化，最终发展为肝细胞癌(hepatocellular carcinoma，HCC)。肝脏中脂肪酸过度累积会引发一系列肝细胞死亡并加剧NAFLD的进展，其中细胞焦亡和凋亡被视为NAFLD进展的关键事件。新近研究发现：胱天蛋白酶-3(cysteine aspartic acid specific protease-3，caspase-3)是调控NAFLD中细胞焦亡和凋亡的关键枢纽，活化的caspase-3不仅直接导致细胞凋亡，还可切割焦孔素E(gasdermin E，GSDME)的N端结构域，破坏细胞膜，释放炎症因子，介导细胞焦亡。抑制NAFLD中caspase-3的表达可减缓肝细胞中细胞损伤(如肝细胞气球样变)、促炎信号转导以及细胞凋亡，caspase-3可能是调控肝细胞焦亡和凋亡的关键，有望成为防治NAFLD的新靶点。

Abstract

Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and advanced fibrosis, is a leading cause of chronic liver disease worldwide, progressing to cirrhosis and ultimately hepatocellular carcinoma (HCC). Excessive accumulation of fatty acids in the liver triggers multiple forms of hepatocyte death and exacerbates NAFLD progression, with pyroptosis and apoptosis considered key events. Recent studies show that cysteine aspartic acid specific protease-3 (caspase-3) is a central regulator of both pyroptosis and apoptosis in NAFLD. Activated caspase-3 not only directly induces apoptosis but also cleaves the N-terminal domain of gasdermin E (GSDME), disrupts cell membranes, releases inflammatory factors, and thereby mediates pyroptosis. Inhibiting caspase-3 expression in NAFLD can alleviate hepatocyte injury (such as ballooning degeneration), dampen pro-inflammatory signaling, and reduce apoptosis. Caspase-3 acts as a key node coordinating pyroptosis and apoptosis and may serve as a novel therapeutic target for the prevention and treatment of NAFLD.

Graphical abstract

关键词

非酒精性脂肪性肝病 / 细胞焦亡 / 细胞凋亡 / 胱天蛋白酶-3 / 串扰

Key words

non-alcoholic fatty liver disease / pyroptosis / apoptosis / caspase-3 / crosstalk

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)是肝脏脂肪蓄积(脂肪变性)所导致的肝脏疾病，为慢性肝损伤^[1]。全球NAFLD的患病率为32%^[2]，其中欧洲患病率最高(54.5%)，其次为亚洲(39.9%)和北美洲(29.1%)^[3]；中国NAFLD患病率为29.2%^[4]。随着发病率的持续上升，NAFLD已成为全球公共卫生领域的一大挑战。

NAFLD的发病机制复杂，尚未完全阐明。肝细胞内脂肪酸的异常积聚可引发脂毒性，促进氧化应激反应，进而导致肝功能受损及炎症反应，随后引发一系列细胞死亡，加剧NAFLD进展^[5]。新近研究^[6-7]表明细胞焦亡和凋亡在NAFLD发病机制中发挥关键作用。细胞焦亡作为炎症反应模式，会促使大量炎症介质释放，从而加剧肝脏的炎症进程并促进纤维化的发展^[8]。细胞凋亡是有序的细胞自我消亡过程，可由DNA损伤、营养匮乏或氧化应激等细胞受损信号触发，进而激活相应的凋亡通路^[9]，肝细胞可通过产生凋亡相关细胞因子，促进NAFLD的进展^[10]。

胱天蛋白酶(cysteine aspartic acid specific protease，caspase)是半胱氨酸蛋白酶家族的蛋白水解酶，在调控体内细胞死亡中起至关重要的作用。其中caspase-3是一种在胞质溶胶中呈非活性状态的酶原，它通过催化C端半胱氨酸残基的活化，特异性裂解含有天冬氨酸残基的肽键发挥作用。Caspase-3不能通过自剪接或自催化激活，需要由颗粒酶B或其上游caspases在D175位点剪切下小片段后才被部分活化^[11]。活化的caspase-3位于caspase级联反应的末端，是细胞凋亡的关键蛋白^[12]。近年研究^[13-14]发现caspase-3能调控焦孔素E(gasdermin E，GSDME)发挥炎性切割作用，使GSDME的N端结构域破坏，进而破坏细胞膜形成孔隙，释放炎症因子引发细胞焦亡。因此，caspase-3可能是调控细胞焦亡和凋亡的核心。

1 <bold>Caspase-3</bold>调控肝细胞焦亡促进<bold>NAFLD</bold>的发生和发展

细胞焦亡是一种由焦孔素(gasdermin，GSDM)家族蛋白介导的程序性细胞死亡，其特点包括细胞膜破裂形成孔隙、细胞肿胀、DNA断裂以及促炎症细胞因子的释放^[15]。研究^[16]表明：细胞焦亡促进NAFLD的发生和发展，使其进展为非酒精性脂肪性肝炎(non-alcoholic steatohepatitis，NASH)。

目前，共发现3种途径导致肝细胞焦亡：第1种是caspase-1/GSDMD介导的经典途径。NAFLD发生时，核苷酸结合寡聚化结构域样受体蛋白 3(nucleotide-binding oligomerization domain-like receptor protein 3，NLRP3)在肝免疫细胞中被激活，进而激活caspase-1，切割GSDMD后使其N端结构域锚定于细胞膜上形成焦亡孔，导致细胞发生焦亡^[17-18]。白细胞介素(interleukin，IL)-1β和IL-18通过孔隙逸出，触发肝脏的炎症反应^[19]。第2种是 caspase-4/5/11/GSDMD介导的非经典途径。肝脏通过门静脉系统持续暴露于低水平脂多糖(lipopolysaccharide，LPS)环境中，驱动NAFLD等肝脏疾病中炎症小体的激活^[7]。第3种是caspase-3依赖性焦亡途径。Wang等^[13]发现GSDME中存在caspase-3四肽切割位点。在GSDME高水平表达的情况下，活化的caspase-3会切割并激活GSDME，释放出能与膜磷脂结合的、具有打孔功能的N端片段，进而破坏细胞膜，触发细胞焦亡^[20]。

Caspase-3依赖性焦亡途径调控的肝细胞焦亡，在NAFLD的炎性进展中发挥重要作用。研究者^[21-22]在蛋氨酸-胆碱缺乏饮食(methionine-choline deficient diet，MCD)喂养的小鼠中观察到肝脏脂肪堆积，且证明这些变化与肝细胞中活化的caspase-3表达显著增加有关。用MCD喂养的caspase-3缺陷型小鼠促炎信号转导显著降低，炎症性巨噬细胞浸润和促炎细胞因子的生成减少^[22]。Zhang等^[23]研究发现丹参新酮可通过caspase-3/GSDME通路诱导肝细胞癌(hepatocellular carcinoma，HCC)中的细胞焦亡发挥抗癌作用。高水平葡萄糖能通过caspase-3/GSDME通路诱导肝细胞焦亡进而发生糖尿病肝损伤^[24]。Mao等^[25]发现脱氧雪腐镰刀菌烯醇(deoxynivalenol，DON)可诱导肝细胞中caspase-3/GSDME依赖性焦亡和炎性细胞因子分泌，加重肝脏炎症反应并导致肝脏严重炎症损伤，在使用caspase-3抑制剂Z-DEVD-FMK抑制其活性后，DON诱导的肝脏炎症损伤减轻，小鼠肝脏中GSDME活性显著下调，表明Z-DEVD-FMK阻断了DON诱导的caspase-3依赖性肝细胞焦亡。使用 GSDME衍生的caspase-3抑制剂Ac-DMLD-CMK抑制caspase-3及其下游效应子GSDME的激活来研究肝细胞焦亡的变化，结果显示Ac-DMLD-CMK减轻了肝损伤、氧化应激和caspase-3/GSDME介导的焦亡^[26]。还有证据^[27]表明抑制caspase-3/GSDME介导的细胞焦亡可保护小鼠免受肝内胆汁淤积相关的急性肝衰竭。Caspase-3调控肝细胞焦亡的机制见图1。

2 <bold>Caspase-3</bold>调控肝细胞凋亡促进<bold>NAFLD</bold>的发生和发展

细胞凋亡是一种程序性细胞死亡，能终止细胞生命，可分为内源性和外源性途径^[28]，并激活caspase家族成员。肝细胞凋亡会导致肝脏炎症和纤维化^[29]。

内源性途径的特征是线粒体外膜通透化(mitochondrial outer membrane permeablisation，MOMP)并释放细胞色素c(cytochrome c，Cyt c)^[30]，其发生与抗凋亡蛋白B细胞淋巴瘤2(B-cell lymphoma-2，Bcl-2)的表达密切相关^[31]。Cyt c可激活Bcl-2相关X蛋白(Bcl-2-associated X，Bax)、Bcl-2相互作用细胞死亡介质(Bcl-2 interacting mediator of cell death，Bim)等促凋亡蛋白^[32]，其表达的上调在NAFLD的细胞凋亡中起重要作用。外源性细胞凋亡途径由细胞外微环境的扰动触发，此过程涉及细胞表面死亡受体(death receptor，DR)的激活，最终导致细胞凋亡的发生^[33]。同时，DR复合物能激活Bcl-2蛋白家族成员BH3相互作用域死亡激动剂(BH3 interacting domain death agonist，Bid)从而间接激活caspase级联反应，产生对内源性途径的反馈并促进MOMP^[34-35]。Caspase级联反应激活末端caspase-3，同时DRs激活caspase-8，caspase-8可裂解纯化Bid，触发内源性途径细胞凋亡释放Cyt c，从而再次激活caspase-3^[36]。

活化的caspase-3通过使DNA断裂、激活聚腺苷二磷酸核糖聚合酶[poly (ADP-ribose) polymerase，PARP]和引发核碎裂等诱导细胞发生凋亡^[37]。与正常个体相比，NAFLD患者中末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法(terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling，TUNEL)染色的阳性肝细胞数显著增加caspase-3活性水平显著升高，NAFLD的各种动物模型也显示肝脏中caspase-3水平升高、线粒体Cyt c上调^{[7, 38]}。Barreyro等^[39]通过给予小鼠高脂饮食(high-fat diet，HFD)诱导NAFLD，发现小鼠肝脏中的脂质过氧化产物水平上升，TUNEL检测到细胞凋亡的存在，并观察到caspase-3的活性增强。Thapaliya等^[22]饲喂MCD诱发小鼠NAFLD，与野生型小鼠相比，caspase-3敲除小鼠肝细胞损伤(如肝细胞气球样变)和细胞凋亡水平降低，促炎信号转导和炎症性巨噬细胞浸润减少。添加泛半胱天冬酶抑制剂能够显著减轻HFD喂养小鼠肝损伤、炎症反应、纤维化程度，以及减少细胞凋亡的发生^[39]。Caspase-3调控肝细胞凋亡的机制见图1。

3 <bold>Caspase-3</bold>调控细胞焦亡与凋亡之间的串扰

细胞死亡是众多疾病进展的关键事件之一。以往认为细胞焦亡和凋亡等死亡子程序是相互独立的，但新近研究^[7]提示细胞焦亡和凋亡之间存在重叠和串扰。越来越多证据^[40-41]表明：凋亡相关信号通路的激活参与焦亡的发生，而焦亡的发生也可伴随凋亡。凋亡细胞不仅能促进自身的吞噬作用，还能抑制炎症。在细胞凋亡中检测到金属蛋白酶(如ADAM10/17)等脱落的细胞表面蛋白，可通过产生可溶性受体发挥抗炎作用^[42-43]。在巨噬细胞中，细胞凋亡激活的泛联蛋白1通道能驱动炎症小体的激活^[44]。在GSDMD缺陷型巨噬细胞中，激活的caspase-1可裂解Bcl-2家族蛋白成员Bid，导致MOMP激活、Cyt c释放和下游凋亡信号转导，细胞死亡方式由炎症介质诱导的细胞焦亡转变为细胞凋亡，表明存在caspase-1驱动的细胞凋亡通路^[45-46]。在LPS诱导小鼠休克和大肠杆菌败血症中，靶组织中的肿瘤坏死因子和Ⅰ型干扰素诱导caspase-8和caspase-11协同促进细胞焦亡和凋亡，放大组织损伤相关的炎症信号诱导死亡^[47]。Wang等^[48]发现丝氨酸-苏氨酸激酶介导的NLRP3炎症小体/caspase-1/IL-1β通路激活能导致心肌细胞和原代人心脏成纤维细胞发生焦亡和凋亡，从而促进心肌梗死的发展。Li等^[49]发现芹菜素可以保护心肌细胞免受缺血缺氧诱导的心肌损伤，保护作用很可能与细胞焦亡、细胞凋亡和促炎细胞因子的减少有关。Sun等^[50]研究发现caspase-3抑制剂可抑制大脑中动脉闭塞大鼠细胞凋亡并延缓脑细胞坏死及炎症小体的释放。

Caspase-3/GSDME信号通路作为“开关”，在细胞内GSDME过度表达的情况下，活化的caspase-3会触发细胞焦亡过程；在GSDME表达水平较低的细胞中，活化的caspase-3则主要诱导细胞发生凋亡^[13-14]。Corey等^[51]发现未被巨噬细胞清除的凋亡小体可通过caspase-3介导GSDME的裂解发生继发性焦亡，导致细胞死亡。Yu等^[52]研究发现：抗肿瘤药物洛铂能激活活性氧和c-Jun末端激酶，使Bax向线粒体聚集，促进Cyt c释放，诱导caspase-3裂解活化，从而触发细胞凋亡。被活化的caspase-3进一步切割GSDME，生成GSDME-N片段，在细胞膜上形成孔隙释放炎症因子，最终诱导癌细胞发生焦亡。该研究还发现敲除HT-29细胞中的GSDME可将洛铂诱导的细胞死亡方式从焦亡转变为凋亡。同样，在敲除GSDME的BALB/c裸鼠中，洛铂诱导的细胞焦亡也可转化为细胞凋亡^[52]。土木香内酯可通过下调甲状腺未分化癌细胞周期相关蛋白诱导细胞周期停滞在G2/M期，并激活caspase-3上调促凋亡蛋白表达(如降低Bcl-2/Bax比率、释放Cyt c)和裂解GSDME，进一步诱导细胞焦亡和凋亡^[53]。一项蛇床子素诱导细胞死亡抑制癌细胞生长的研究^[54]中，蛋白质组学结果表明蛇床子素能提高caspase-3的表达，而抑制caspase-3不仅减少蛇床子素诱导的细胞凋亡，还能抑制GSDME介导的细胞焦亡。也有研究^{[11, 55]}提出GSDME可能是caspase-3的上游，连接外源性和内源性凋亡途径，促进caspase-3激活，形成前馈环持续激活细胞焦亡和凋亡。Tsuchiya等^[46]发现细胞焦亡和凋亡的另一串扰，在GSDMD缺陷型巨噬细胞中，被广泛认为是引发细胞焦亡的caspase-1可激活Bid/caspase-9/caspase-3轴启动细胞凋亡，同时还可引发GSDME介导的继发性焦亡，但caspase-1是如何触发caspase-3激活和进一步的细胞死亡的有待阐明。

已有研究指出，在肝脏疾病中caspase-3能同时调控细胞焦亡和凋亡，如Zheng等^[56]的研究表明：二甲双胍通过诱导线粒体功能障碍，在人肝癌细胞HepG2中触发细胞焦亡和升高乳酸脱氢酶水平(焦亡细胞毒性现象)，这个过程启动了caspase-3介导的GSDME切割，同时导致Bax表达升高和Cyt c释放以启动细胞焦亡和凋亡。Zhang等^[23]认为米替龙通过抑制丝裂原活化蛋白激酶和细胞外调节蛋白激酶的磷酸化，导致细胞内活性氧积累，激活小鼠HCC细胞系Hepa1~6中的caspase-3，促进Bax表达和GSDME诱导的细胞焦亡。Wang等^[24]研究发现抑制caspase-3可减轻高葡萄糖诱导的小鼠肝细胞AML-12中细胞焦亡和凋亡水平，从而改善肝细胞损伤。一项对脓毒性肝损伤小鼠的研究^[26]发现：抑制caspase-3的表达可降低细胞焦亡和凋亡水平，减轻肝损伤。

4 结 语

肝细胞焦亡和凋亡是NAFLD发生、发展中的核心事件，caspase-3是调控细胞焦亡和凋亡及改善肝细胞损伤的关键因子，是防治NAFLD的新靶点。然而，caspase-3在NAFLD中的研究仍面临诸多挑战，如caspase-3介导的焦亡和凋亡在NAFLD不同疾病阶段的双重调控作用有待揭示；caspase-3抑制剂(如Ac-DEVD-CHO)缺乏细胞特异性等。未来可利用单细胞测序和活细胞成像等技术阐明caspase-3动态调控网络，开发具有细胞特异性的caspase-3抑制剂及相关药物，建立基于多组学整合的caspase-3活性评估体系，为NAFLD的精准防治提供新思路。

参考文献

[1] 薛芮, 范建高. 代谢相关脂肪性肝病新定义的国际专家共识简介[J]. 实用肝脏病杂志, 2020, 23(3): 457-460.

[2] XUE Rui, FAN Jiangao. Brief introduction of an international expert consensus statement: a new definition of metabolic associated fatty liver disease[J]. Journal of Practical Hepatology, 2020, 23(3): 457-460.

[3] Riazi K, Azhari H, Charette JH, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis[J]. Lancet Gastroenterol Hepatol, 2022, 7(9): 851-861.

[4] Lim GEH, Tang A, Ng CH, et al. An observational data meta-analysis on the differences in prevalence and risk factors between MAFLD vs NAFLD[J/OL]. Clin Gastroenterol Hepatol, 2023, 21(3): 619-629.e7[2024-10-21].

[5] Man S, Deng Y, Ma Y, et al. Prevalence of liver steatosis and fibrosis in the general population and various high-risk populations: a nationwide study with 5.7 million adults in China[J]. Gastroenterology, 2023, 165(4): 1025-1040.

[6] Guo X, Yin X, Liu Z, et al. Non-alcoholic fatty liver disease (NAFLD) pathogenesis and natural products for prevention and treatment[J]. Int J Mol Sci, 2022, 23(24): 15489.

[7] Li SJ, Liu AB, Yu YY, et al. The role and mechanism of pyroptosis and potential therapeutic targets in non-alcoholic fatty liver disease (NAFLD)[J]. Front Cell Dev Biol, 2024, 12: 1407738.

[8] Shojaie L, Iorga A, Dara L. Cell death in liver diseases: a review[J]. Int J Mol Sci, 2020, 21(24): 9682.

[9] Feng Y, Li W, Wang Z, et al. The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis[J]. J Transl Med, 2022, 20(1): 497.

[10] Ketelut-Carneiro N, Fitzgerald KA. Apoptosis, pyroptosis, and necroptosis-oh my! the many ways a cell can die[J]. J Mol Biol, 2022, 434(4): 167378.

[11] Nasiri-Ansari N, Nikolopoulou C, Papoutsi K, et al. Empagliflozin attenuates non-alcoholic fatty liver disease (NAFLD) in high fat diet fed ApoE(-/-) mice by activating autophagy and reducing ER stress and apoptosis[J]. Int J Mol Sci, 2021, 22(2): 818.

[12] Jiang M, Qi L, Li L, et al. The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer[J]. Cell Death Discov, 2020, 6: 112.

[13] Araya LE, Soni IV, Hardy JA, et al. Deorphanizing caspase-3 and caspase-9 substrates in and out of apoptosis with deep substrate profiling[J]. ACS Chem Biol, 2021, 16(11): 2280-2296.

[14] Wang Y, Gao W, Shi X, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin[J]. Nature, 2017, 547(7661): 99-103.

[15] Zheng X, Zhong T, Ma Y, et al. Bnip3 mediates doxorubicin-induced cardiomyocyte pyroptosis via caspase-3/GSDME[J]. Life Sci, 2020, 242: 117186.

[16] Vasudevan SO, Behl B, Rathinam VA. Pyroptosis-induced inflammation and tissue damage[J]. Semin Immunol, 2023, 69: 101781.

[17] de Carvalho Ribeiro M, Szabo G. Role of the inflammasome in liver disease[J]. Annu Rev Pathol, 2022, 17: 345-365.

[18] Wang K, Sun Q, Zhong X, et al. Structural mechanism for GSDMD targeting by autoprocessed caspases in pyroptosis [J/OL]. Cell, 2020, 180(5): 941-955.e20[2024-10-19].

[19] 王丹, 刘袁洪, 宗秀乐, 等. 酸化脂肪酸酯通过抑制NLRP3炎症小体活化减少脓毒症致死[J]. 中南大学学报(医学版), 2023, 48(6): 809-820.

[20] WANG Dan, LIU Yuanhong, ZONG Xiule, et al. Ozonated triglyceride protects against septic lethality via preventing the activation of NLRP3 inflammasome[J]. Journal of Central South University. Medical Science, 2023, 48(6): 809-820.

[21] Wang J, Sun Z, Xie J, et al. Inflammasome and pyroptosis in autoimmune liver diseases[J]. Front Immunol, 2023, 14: 1150879.

[22] Ji N, Qi Z, Wang Y, et al. Pyroptosis: a new regulating mechanism in cardiovascular disease[J]. J Inflamm Res, 2021, 14: 2647-2666.

[23] Nanji AA. Animal models of nonalcoholic fatty liver disease and steatohepatitis[J]. Clin Liver Dis, 2004, 8(3): 559-574.

[24] Thapaliya S, Wree A, Povero D, et al. Caspase 3 inactivation protects against hepatic cell death and ameliorates fibrogenesis in a diet-induced NASH model[J]. Dig Dis Sci, 2014, 59(6): 1197-1206.

[25] Zhang X, Zhang P, An L, et al. Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis[J]. Acta Pharm Sin B, 2020, 10(8): 1397-1413.

[26] Wang X, Ye S, Tong L, et al. Inhibition of ROS/caspase- 3/GSDME-mediated pyroptosis alleviates high glucose-induced injury in AML-12 cells[J]. Toxicol In Vitro, 2024, 98: 105840.

[27] Mao X, Li J, Xie X, et al. Deoxynivalenol induces caspase- 3/GSDME-dependent pyroptosis and inflammation in mouse liver and HepaRG cells[J]. Arch Toxicol, 2022, 96(11): 3091-3112.

[28] Lu N, Qin H, Meng Z, et al. Inhibiting apoptosis and GSDME-mediated pyroptosis attenuates hepatic injury in septic mice[J]. Arch Biochem Biophys, 2024, 754: 109923.

[29] Xu W, Zhang Q, Ding C, et al. Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure[J]. Acta Pharmacol Sin, 2021, 42(1): 68-76.

[30] Newton K, Strasser A, Kayagaki N, et al. Cell death[J]. Cell, 2024, 187(2): 235-256.

[31] LeFort KR, Rungratanawanich W, Song BJ. Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction[J]. Cell Mol Life Sci, 2024, 81(1): 34.

[32] Green DR. The mitochondrial pathway of apoptosis[J]. Cold Spring Harb Perspect Biol, 2022, 14(5): a041038.

[33] King LE, Hohorst L, García-Sáez AJ. Expanding roles of BCL-2 proteins in apoptosis execution and beyond[J]. J Cell Sci, 2023, 136(22): jcs260790.

[34] Wolf P, Schoeniger A, Edlich F. Pro-apoptotic complexes of BAX and BAK on the outer mitochondrial membrane[J]. Biochim Biophys Acta Mol Cell Res, 2022, 1869(10): 119317.

[35] Green DR. The death receptor pathway of apoptosis[J]. Cold Spring Harb Perspect Biol, 2022, 14(2): a041053.

[36] Lossi L. The concept of intrinsic versus extrinsic apoptosis[J]. Biochem J, 2022, 479(3): 357-384.

[37] Alkhouri N, Alisi A, Okwu V, et al. Circulating soluble fas and fas ligand levels are elevated in children with nonalcoholic steatohepatitis[J]. Dig Dis Sci, 2015, 60(8): 2353-2359.

[38] Zhao P, Sun X, Chaggan C, et al. An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis[J]. Science, 2020, 367(6478): 652-660.

[39] Sahoo G, Samal D, Khandayataray P, et al. A review on caspases: key regulators of biological activities and apoptosis[J]. Mol Neurobiol, 2023, 60(10): 5805-5837.

[40] Hatting M, Zhao G, Schumacher F, et al. Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents[J]. Hepatology, 2013, 57(6): 2189-2201.

[41] Barreyro FJ, Holod S, Finocchietto PV, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis[J]. Liver Int, 2015, 35(3): 953-966.

[42] Broz P. Immunology: Caspase target drives pyroptosis[J]. Nature, 2015, 526(7575): 642-643.

[43] Xu X, Zhang T, Xia X, et al. Pyroptosis in periodontitis: From the intricate interaction with apoptosis, NETosis, and necroptosis to the therapeutic prospects[J]. Front Cell Infect Microbiol, 2022, 12: 953277.

[44] Bertheloot D, Latz E, Franklin BS. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death[J]. Cell Mol Immunol, 2021, 18(5): 1106-1121.

[45] Sui C, Zhou D. ADAM metallopeptidase domain 10 knockdown enables podocytes to resist high glucose stimulation by inhibiting pyroptosis via MAPK pathway[J]. Exp Ther Med, 2023, 25(6): 260.

[46] Chen KW, Demarco B, Heilig R, et al. Extrinsic and intrinsic apoptosis activate pannexin-1 to drive NLRP3 inflammasome assembly[J/OL]. EMBO J, 2019, 38(10): e101638[2024-09-08].

[47] de Vasconcelos NM, Van Opdenbosch N, Van Gorp H, et al. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture[J]. Cell Death Differ, 2019, 26(1): 146-161.

[48] Tsuchiya K, Nakajima S, Hosojima S, et al. Caspase-1 initiates apoptosis in the absence of gasdermin D[J]. Nat Commun, 2019, 10(1): 2091.

[49] Mandal P, Feng YJ, Lyons JD, et al. Caspase-8 collaborates with caspase-11 to drive tissue damage and execution of endotoxic shock[J/OL]. Immunity, 2018, 49(1): 42-55.e6[2024-09-30].

[50] Wang SH, Cui LG, Su XL, et al. GSK-3β-mediated activation of NLRP3 inflammasome leads to pyroptosis and apoptosis of rat cardiomyocytes and fibroblasts[J]. Eur J Pharmacol, 2022, 920: 174830.

[51] Li W, Chen L, Xiao Y. Apigenin protects against ischemia-/hypoxia- induced myocardial injury by mediating pyroptosis and apoptosis[J]. In Vitro Cell Dev Biol Anim, 2020, 56(4): 307-312.

[52] Sun Y, Xu Y, Geng L. Caspase-3 inhibitor prevents the apoptosis of brain tissue in rats with acute cerebral infarction[J]. Exp Ther Med, 2015, 10(1): 133-138.

[53] Paik JM, Golabi P, Younossi Y, et al. Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD[J]. Hepatology, 2020, 72(5): 1605-1616.

[54] Yu J, Li S, Qi J, et al. Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells[J]. Cell Death Dis, 2019, 10(3): 193.

[55] Hu Y, Wen Q, Cai Y, et al. Alantolactone induces concurrent apoptosis and GSDME-dependent pyroptosis of anaplastic thyroid cancer through ROS mitochondria-dependent caspase pathway[J]. Phytomedicine, 2023, 108: 154528.

[56] Wang J, Huangfu M, Li X, et al. Osthole induces apoptosis and caspase-3/GSDME-dependent pyroptosis via NQO1-mediated ROS generation in HeLa cells[J]. Oxid Med Cell Longev, 2022, 2022: 8585598.

[57] Li L, Wang S, Zhou W. Balance cell apoptosis and pyroptosis of caspase-3-activating chemotherapy for better antitumor therapy[J]. Cancers (Basel), 2022, 15(1): 26.

[58] Zheng Z, Bian Y, Zhang Y, et al. Metformin activates AMPK/SIRT1/NF-κB pathway and induces mitochondrial dysfunction to drive caspase3/GSDME-mediated cancer cell pyroptosis[J]. Cell Cycle, 2020, 19(10): 1089-1104.

基金资助

湖南省自然科学基金(2023JJ60306)

湖南省卫生健康委科研计划项目(202112022208)

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