Cholestasis is primarily caused by bile acid homeostasis dysregulation, resulting in retention, aggregation, and accumulation of the toxic cholate in the hepatocytes. Existing therapies for cholestasis are limited, demanding the urgent development of novel drugs. As a result, targeting FXR specifically promises a unique treatment strategy for cholestasis. The current study aims to evaluate the influence of 7, 8-dihydroxy-4-methyl coumarin (DMC) against alpha-naphthyl isothiocyanate (ANIT)-induced liver injury in mice. The “Computer-Aided Drug Design” (CADD) and molecular docking study anticipated that DMC would proficiently bind and activate the FXR. Accordingly, the hepatoprotective activity of DMC against ANIT-induced hepatotoxicity and cholestasis was investigated in ANIT-treated HepaRG cells and the ANIT-induced cholestatic mouse model. Outcomes indicated the protective effects of DMC against ANIT toxicity in HepaRG cells after 24 h of intervention and animals after seven days of treatment. DMC partially blocks ANIT-induced increases in serum markers of hepatocellular injury, liver and gall bladder enlargement, and hepatic necrosis. Western blotting revealed that DMC alleviates ANIT-induced hepatotoxicity and cholestasis via activating the FXR receptor and regulating CYP7A1, the enzyme responsible for bile acid synthesis. DMC exhibited protective activity against cholestasis through activating FXR, suggesting it might be a promising strategy for preventing and treating cholestatic liver disease.

胆汁淤积主要由胆汁酸稳态失调引起，导致有毒胆酸盐在肝细胞中滞留、聚集和积累。现有的胆汁淤积疗法有限，迫切需要开发新药。因此，以 FXR 为目标特别有望成为一种独特的胆汁淤积治疗策略。目前的研究旨在评估 7, 8-二羟基-4-甲基香豆素 (DMC) 对 α-萘基异硫氰酸酯 (ANIT) 诱导的小鼠肝损伤的影响。“计算机辅助药物设计”（CADD）和分子对接研究预计 DMC 将熟练地结合并激活 FXR。因此，在 ANIT 处理的 HepaRG 细胞和 ANIT 诱导的胆汁淤积小鼠模型中研究了 DMC 对 ANIT 诱导的肝毒性和胆汁淤积的保肝活性。结果表明，干预 24 小时后 DMC 对 HepaRG 细胞和治疗 7 天后动物的 ANIT 毒性具有保护作用。DMC 部分阻断 ANIT 诱导的肝细胞损伤、肝脏和胆囊肿大以及肝坏死的血清标志物的增加。Western blotting 显示，DMC 通过激活 FXR 受体和调节 CYP7A1（负责胆汁酸合成的酶）来减轻 ANIT 诱导的肝毒性和胆汁淤积。DMC 通过激活 FXR 表现出对胆汁淤积的保护活性，表明它可能是预防和治疗胆汁淤积性肝病的一种有前途的策略。DMC 部分阻断 ANIT 诱导的肝细胞损伤、肝脏和胆囊肿大以及肝坏死的血清标志物的增加。Western blotting 显示，DMC 通过激活 FXR 受体和调节 CYP7A1（负责胆汁酸合成的酶）来减轻 ANIT 诱导的肝毒性和胆汁淤积。DMC 通过激活 FXR 表现出对胆汁淤积的保护活性，表明它可能是预防和治疗胆汁淤积性肝病的一种有前途的策略。DMC 部分阻断 ANIT 诱导的肝细胞损伤、肝脏和胆囊肿大以及肝坏死的血清标志物的增加。Western blotting 显示，DMC 通过激活 FXR 受体和调节 CYP7A1（负责胆汁酸合成的酶）来减轻 ANIT 诱导的肝毒性和胆汁淤积。DMC 通过激活 FXR 表现出对胆汁淤积的保护活性，表明它可能是预防和治疗胆汁淤积性肝病的一种有前途的策略。