Lin Qian, Zhang Jiaren, Qi Jie, Tong Jialin, Chen Shenghuan, Zhang Sudan, Liu Xingru, Lou Huatong, Lv Jiaxuan, Lin Ruoyu, Xie Junjun, Jin Yi, Wang Yang, Ying Lei, Wu Jiamin, Niu Jianlou
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.
Adv Sci (Weinh). 2025 Feb;12(7):e2408688. doi: 10.1002/advs.202408688. Epub 2024 Dec 27.
Isoniazid and rifampicin co-therapy are the main causes of anti-tuberculosis drug-induced liver injury (ATB-DILI) and acute liver failure, seriously threatening human health. However, its pathophysiology is not fully elucidated. Growing evidences have shown that fibroblast growth factors (FGFs) play a critical role in diverse aspects of liver pathophysiology. The aim of this study is to investigate the role of FGFs in the pathogenesis of isoniazid (INH) and rifampicin (RIF)-induced liver injury. Through systematic screening, this study finds that hepatic FGF1 expression is significantly downregulated in both mouse model and human patients challenged with INH and RIF. Hepatocyte-specific Fgf1 deficiency exacerbates INH and RIF-induced liver injury resulted from elevated bile acids (BAs) synthases and aberrant BAs accumulation. Conversely, pharmacological administration of the non-mitogenic FGF1 analog - FGF1 significantly alleviated INH and RIF-induced liver injury via restoring BAs homeostasis. Mechanically, FGF1 repressed hepatocyte nuclear factor 4α (Hnf4α) transcription via activating FGF receptor 4 (FGFR4)-ERK1/2 signaling pathway, thus reducing BAs synthase. The findings demonstrate hepatic FGF1 functions as a negative regulator of BAs biosynthesis to protect against INH and RIF-induced liver injury via normalizing hepatic BAs homeostasis, providing novel mechanistic insights into the pathogenesis of ATB-DILI and potential therapeutic strategies for treatment of ATB-DILI.
异烟肼和利福平联合治疗是抗结核药物性肝损伤（ATB - DILI）和急性肝衰竭的主要原因，严重威胁人类健康。然而，其病理生理学尚未完全阐明。越来越多的证据表明，成纤维细胞生长因子（FGFs）在肝脏病理生理学的各个方面发挥着关键作用。本研究的目的是探讨FGFs在异烟肼（INH）和利福平（RIF）诱导的肝损伤发病机制中的作用。通过系统筛选，本研究发现，在接受INH和RIF攻击的小鼠模型和人类患者中，肝脏FGF1表达均显著下调。肝细胞特异性Fgf1缺乏会加剧因胆汁酸（BAs）合成酶升高和BAs异常积累而导致的INH和RIF诱导的肝损伤。相反，非促有丝分裂FGF1类似物 - FGF1的药理学给药通过恢复BAs稳态显著减轻了INH和RIF诱导的肝损伤。在机制上，FGF1通过激活FGF受体4（FGFR4） - ERK1/2信号通路抑制肝细胞核因子4α（Hnf4α）转录，从而减少BAs合成酶。这些发现表明，肝脏FGF1作为BAs生物合成的负调节因子，通过使肝脏BAs稳态正常化来保护免受INH和RIF诱导的肝损伤，为ATB - DILI的发病机制提供了新的机制见解和治疗ATB - DILI的潜在治疗策略。
