Hepatocyte-Derived FGF1 Alleviates Isoniazid and Rifampicin-Induced Liver Injury by Regulating HNF4α-Mediated Bile Acids Synthesis

  • Adv Sci (Weinh). 2024 Dec 27:e2408688. doi: 10.1002/advs.202408688.
Qian Lin  1 ,  Jiaren Zhang  1 ,  Jie Qi  1 ,  Jialin Tong  1 ,  Shenghuan Chen  1 ,  Sudan Zhang  1 ,  Xingru Liu  1 ,  Huatong Lou  1 ,  Jiaxuan Lv  1 ,  Ruoyu Lin  1 ,  Junjun Xie  2 ,  Yi Jin  3 ,  Yang Wang  4 ,  Lei Ying  4 ,  Jiamin Wu  1 ,  Jianlou Niu  1
Affiliations
  • 1. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 2. Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.
  • 3. Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 4. School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
PMID: 39731358 DOI: 10.1002/advs.202408688
Abstract

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 - FGF1ΔHBS 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.

Keywords
FGFR4; Fibroblast growth factors; HNF4α; anti‐tuberculosis drug‐induced liver injury; bile acids biosynthesis.
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