TMEM121通过激活NLRP3/caspase-1/GSDMD通路加剧对乙酰氨基酚诱导的肝癌细胞焦亡

doi:10.16288/j.yczz.25-348

遗传 ›› 2026, Vol. 48 ›› Issue (10): 986-998.doi: 10.16288/j.yczz.25-348

TMEM121通过激活NLRP3/caspase-1/GSDMD通路加剧对乙酰氨基酚诱导的肝癌细胞焦亡

何国良¹(), 杨威¹, 吴林晓¹, 梁锦成⁵, 姚峰⁶, 周军媚¹^,²^,³^,⁴()

¹ 桂林医科大学第一附属医院，广西肝脏损伤与修复分子医学重点实验室，桂林 541001
² 桂林医科大学第一附属医院，广西神经鞘脂代谢相关疾病基础研究重点实验室，桂林 541001
³ 桂林医科大学中美健康与疾病脂质研究中心，桂林 541001
⁴ 桂林医科大学第一附属医院，肝胆胰外科实验室，桂林 541001
⁵ 桂林医科大学临床医学院，桂林 541001
⁶ 桂林医科大学实验动物中心，桂林 541001

收稿日期:2026-03-13 修回日期:2026-05-19 出版日期:2026-07-29 发布日期:2026-07-29
通讯作者: 周军媚，博士，副研究员，研究方向：肝脏再生。E-mail: junmeizh@glmu.edu.cn
作者简介:何国良，硕士研究生，专业方向：外科学。E-mail: 1643872563@qq.com
基金资助:
国家自然科学基金项目(82060124);国家自然科学基金项目(82260529);桂林医科大学校创新创业训练计划项目(202410601009)

TMEM121 aggravates acetaminophen-induced pyroptosis in hepatocellular carcinoma cells by activating the NLRP3/caspase-1/GSDMD pathway

Guoliang He¹(), Wei Yang¹, Linxiao Wu¹, Jincheng Liang⁵, Feng Yao⁶, Junmei Zhou¹^,²^,³^,⁴()

¹ Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The First Affiliated Hospital of Guilin Medical University, Guilin 541001, China
² Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The First Affiliated Hospital of Guilin Medical University, Guilin 541001, China
³ China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, China
⁴ Laboratory of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Guilin Medical University Guilin 541001, China
⁵ Clinical Medical College, Guilin Medical University, Guilin 541001, China
⁶ Laboratory Animal Center, Guilin Medical University, Guilin 541001, China

Received:2026-03-13 Revised:2026-05-19 Published:2026-07-29 Online:2026-07-29
Supported by:
National Natural Science Foundation of China(82060124);National Natural Science Foundation of China(82260529);Innovation and Entrepreneurship Training Initiative of Guilin Medical University(202410601009)

摘要/Abstract

摘要：

对乙酰氨基酚(acetaminophen，APAP)是常见的解热镇痛药，但其过量使用可导致严重的药物性肝损伤。人跨膜蛋白121(transmembrane protein121，TMEM121)是一种进化保守的跨膜蛋白，在肝脏组织中有较显著的表达，但其在肝脏损伤中的功能未知。为探讨TMEM121基因在APAP诱导的肝癌细胞损伤中的作用及其分子机制，本研究综合运用生物信息学预测、细胞功能实验和焦亡通路关键分子检测等方法进行了分析。首先，通过分子对接分析，发现TMEM121蛋白与APAP存在直接结合能力；GSE104601数据集分析及细胞实验证实，APAP负调控TMEM121基因的表达。在APAP刺激下，TMEM121过表达增加了Huh7细胞对APAP的敏感性，且逆转了TMEM121在未受刺激时对细胞增殖与迁移的促进作用。在机制探讨方面，利用蛋白质免疫印迹、ELISA等方法对焦亡通路关键分子进行检测，结果显示在APAP刺激下，TMEM121过表达可上调NLRP3和caspase-1的表达，促进GSDMD发生剪切生成活性片段GSDMD-N，同时显著增加炎症因子IL-1β与IL-18的释放，加剧细胞焦亡的发生。乳酸脱氢酶释放实验及透射电镜观察进一步证实，TMEM121过表达加重了APAP引起的细胞膜损伤，并使细胞呈现细胞膜气泡状凸起、破裂及内容物外溢等典型焦亡形态特征。综上所述，本研究揭示了TMEM121是APAP肝损伤中的一个关键调控因子，通过激活NLRP3/caspase-1/GSDMD信号通路加剧APAP诱导的肝癌细胞焦亡，为深入解析APAP药物性肝损伤的分子机制提供了新的理论依据和潜在靶点。

关键词: TMEM121, 对乙酰氨基酚, 肝癌细胞损伤, 细胞焦亡

Abstract:

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but overdose causes severe acute liver injury. TMEM121 is an evolutionarily conserved transmembrane protein with high expression in liver tissue, yet its role in liver injury remains unknown. To investigate the function and molecular mechanism of the TMEM121 gene in APAP-induced injury in hepatoma carcinoma cells, we comprehensively employed three analytical approaches: bioinformatics prediction, cellular functional assays, and detection of key molecules in the pyroptosis pathway. Firstly, molecular docking analysis revealed that TMEM121 protein can directly bind to APAP. Analysis of the GSE104601 dataset and cellular experiments confirmed that APAP negatively regulates TMEM121 gene expression. Upon APAP stimulation, TMEM121 overexpression increased the sensitivity of Huh7 cells to APAP and reversed the promoting effects of TMEM121 on cell proliferation and migration observed under unstimulated conditions. Mechanistically, Western blotting and ELISA were used to assess key components of the pyroptosis pathway. The results demonstrated that, upon APAP stimulation, TMEM121 overexpression upregulated the expression of NLRP3 and caspase-1, promoted the cleavage of GSDMD to generate the active fragment GSDMD-N, and significantly increased the release of the inflammatory cytokines IL-1β and IL-18, thereby exacerbating pyroptosis. Furthermore, the lactate dehydrogenase release assay and transmission electron microscopy observation confirmed that TMEM121 overexpression aggravated APAP-induced cell membrane damage, leading to characteristic morphological features of pyroptosis, including membrane ballooning, rupture, and leakage of cellular contents. In summary, this study reveals that TMEM121 gene acts as a critical regulator of APAP-induced injury in Huh7 cells by activating the NLRP3/caspase-1/GSDMD signaling pathway and aggravating APAP-induced pyroptosis, providing novel mechanistic insights and potential therapeutic targets for APAP-induced hepatotoxicity.

Key words: TMEM121, acetaminophen, hepatocellular carcinoma cell injury, pyroptosis

何国良, 杨威, 吴林晓, 梁锦成, 姚峰, 周军媚. TMEM121通过激活NLRP3/caspase-1/GSDMD通路加剧对乙酰氨基酚诱导的肝癌细胞焦亡[J]. 遗传, 2026, 48(10): 986-998.

Guoliang He, Wei Yang, Linxiao Wu, Jincheng Liang, Feng Yao, Junmei Zhou. TMEM121 aggravates acetaminophen-induced pyroptosis in hepatocellular carcinoma cells by activating the NLRP3/caspase-1/GSDMD pathway[J]. Hereditas(Beijing), 2026, 48(10): 986-998.

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基因名称	上游引物(5′→3′)	下游引物(5′→3′)
GAPDH	CAGGAGGCATTGCTGATGAT	GAAGGCTGGGGCTCATTT
IL-1β	AGCCATGGCAGAAGTACCTG	CCTGGAAGGAGCACTCATCT
IL-18	ATCGCTTCCTCTCGCAACAA	GTCCGGGGTGCATTATCTCT
TMEM121	CGCCGCAGAAGATGATGCT	CACCACGTTTTTGCCGACG

TMEM121通过激活NLRP3/caspase-1/GSDMD通路加剧对乙酰氨基酚诱导的肝癌细胞焦亡

TMEM121 aggravates acetaminophen-induced pyroptosis in hepatocellular carcinoma cells by activating the NLRP3/caspase-1/GSDMD pathway

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