中国病理生理杂志2026，Vol.42Issue(5)：895-905,11.DOI:10.3969/j.issn.1000-4718.2026.05.007
含三基序蛋白21加剧对乙酰氨基酚诱导的小鼠肝损伤
Tripartite motif containing protein 21 exacerbates acetaminophen-in-duced liver injury in mice
摘要
Abstract
AIM:This study aimed to elucidate the role of tripartite motif containing protein 21(TRIM21)in drug-induced liver injury(DILI)mouse models induced by acetaminophen(APAP).METHODS:The APAP-induced DILI mouse models were established utilizing normal mouse hepatocytes(AML12)as the cellular model and C57BL/6 mice as the animal model.In the cellular model,AML12 cells were treated with APAP at concentrations of 0,2.5,5,7.5 and 12.5 mmol/L for 24 h.Additionally,a TRIM21-overexpressing(OE-TRIM2)mouse cell model was established by transient transfection with a plasmid encoding the mouse TRIM21 gene,and samples were collected 24 h after stimula-tion with 7.5 mmol/L APAP.In the animal model,APAP(400 mg/kg)was administered to induce DILI at various time points(0,6,24 and 48 h).Furthermore,following the establishment of a mouse model overexpressing TRIM21 in the liv-er via tail vein injection of an adeno-associated virus 8(AAV8)overexpressing the mouse TRIM21 gene,APAP(400 mg/kg)was administered intraperitoneally;sampling was conducted after 24 h.Liver injury was evaluated in each animal model group through HE staining.The expression levels of TRIM21,key antioxidant pathway transcription factors,includ-ing nuclear factor E2-related factor 2(Nrf2),quinone oxidoreductase 1(NQO1),glutamate-cysteine ligase catalytic sub-unit(GCLC),glutamate-cysteine ligase modifier subunit(GCLM),glutathione peroxidase 3(GPX3),cytochrome P450 2 E1(CYP2E1),high mobility group box 1(HMGB1),cell cycle suppressor proteins p21 and p16,proliferating cell nu-clear antigen(PCNA),and cyclins(cyclin A,cyclin D and cyclin E)were assessed at the mRNA and protein levels in both the cellular and animal model groups using serum biochemistry,Western blot,real-time quantitative PCR,and im-munohistochemical staining.RESULTS:In the APAP-induced DILI mouse model,TRIM21 expression was significantly upregulated at both the mRNA and protein levels(P<0.05).Functional studies demonstrated that TRIM21 overexpression markedly exacerbated APAP-induced hepatocyte damage in mice.This exacerbated damage was specifically characterized by down-regulation of NRF2 and its downstream target molecules,NQO1,GCLC,GCLM and GPX3,which significantly decreased the antioxidant capacity(P<0.05).Additionally,CYP2E1 was significantly upregulated,further enhancing the toxic metabolism of APAP(P<0.05).Furthermore,TRIM21 overexpression promoted the release of HMGB1 and markedly increased the expression of p21 and p16 but suppressed the expression of PCNA,cyclin A,cyclin D and cyclin E,thereby facilitating cell cycle arrest(P<0.05).CONCLUSION:In the APAP-induced DILI mouse model,TRIM21 expression is increased.This overexpression exacerbates hepatic cell injury,significantly reduces antioxidant capacity,in-tensifies toxic metabolism,and concurrently induces cell cycle arrest.关键词
药物性肝损伤/对乙酰氨基酚/含三基序蛋白21/氧化应激/细胞周期阻滞Key words
drug-induced liver injury/paracetamol/tripartite motif containing protein 21/oxidative stress/cell cycle arrest分类
医药卫生引用本文复制引用
王蓉,周宇霞,刘露,袁菲,黎萍,黄亚莉,扈腊英,王青玉,刘艳,郭兵..含三基序蛋白21加剧对乙酰氨基酚诱导的小鼠肝损伤[J].中国病理生理杂志,2026,42(5):895-905,11.基金项目
国家自然科学基金资助项目(No.82460144) （No.82460144）
贵州省科技计划项目(黔科合支撑[2025]一般113号) （黔科合支撑[2025]一般113号）
贵州省教育厅(青年科技拔尖人才项目)(黔教技[2024]328号) （青年科技拔尖人才项目）
贵州省卫生健康委科学技术基金项目(No.gzwkj2025-278) （No.gzwkj2025-278）
