【摘要】 目的 探究组蛋白去乙酰化酶6(histone deacetylase 6,HDAC6)抑制剂ACY1215对急性肝衰竭(acute liver failure, ALF)小鼠环鸟苷酸-腺苷酸合成酶(cyclic GMP-AMP synthase, cGAS)-干扰素刺激因子(stimulator of interferon genes, STING)通路的作用研究。方法 将30只小鼠随机分为对照组、模型组和ACY1215处理组，采用脂多糖联合D-氨基半乳糖诱导小鼠ALF模型，行血生化、免疫组化和组织病理学检查；采用Western blotting法检测肝组织cGAS和STING蛋白的表达；用ELISA检测TNF-α、IL-1β和IL-18的表达。结果 肝组织病理学检查显示，ALF模型制备成功，而ACY1215干预组肝组织病理学损害较模型组显著减轻；模型组血清ALT和AST水平分别为(1 959.36±90.27)U/L和(2 269.28±181.49)U/L,显著高于对照组，分别为(35.92±5.68)U/L和(59.35±13.52)U/L(P<0.05),而ACY1215处理组ALT和ASL较模型组均显著降低，分别为(680.29±164.93)U/L、(404.81±48.02)U/L(P<0.05);免疫组化、ELISA和Western blotting显示，模型组小鼠肝组织TNF-α、IL-1β、IL-18、cGAS和STING表达较对照组显著升高，而ACY1215干预组肝组织TNF-α、IL-1β、IL-18、cGAS和STING表达较模型组显著减弱。结论 HDAC6抑制剂ACY1215可以通过抑制cGAS-STING通路对ALF小鼠发挥保护作用。更多还原

【Abstract】 Objective To investigate the effect of the histone deacetylase 6(HDAC6) inhibitor ACY1215 on cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) pathway in mice with acute liver failure(ALF) and explore its potential mechanism of action. Methods Thirty mice were randomly divided into control group, model group, and ACY1215 treatment group. The ALF model was induced by intraperitoneal injection of lipopolysaccharide(LPS) and D-galactosamine(D-GalN). Blood biochemical analysis, immunohistochemistry, and histopathological examination were performed. The expression of cGAS and STING in liver tissue was detected by Western blotting. The levels of TNF-α, IL-1β, and IL-18 were measured using ELISA.Results Histopathological examination confirmed successful ALF induction, the ACY1215 treatment group exhibited significantly attenuated liver injury. Serum ALT and AST levels in the model group [(1 959.36±90.27) U/L and(2 269.28±181.49) U/L, respectively] were significantly higher than those in the control group [(35.92±5.68) U/L and(59.35±13.52) U/L, respectively; P<0.05)]. In contrast, ACY1215 treatment markedly reduced ALT and AST levels [(680.29±164.93) U/L and(404.81±48.02) U/L, respectively; P<0.05] compared with model group. Immunohistochemistry, ELISA, and Western blotting analyses revealed that the expression of TNF-α, IL-1β, IL-18, cGAS, and STING in the liver tissue of the model group was significantly elevated compared to the control group, whereas ACY1215 intervention significantly suppressed their expression.Conclusion The HDAC6 inhibitor ACY1215 exerts a protective effect against ALF in mice, likely through inhibition of the cGAS-STING signaling pathway.更多还原