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

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 – FGF1^ΔHBS 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.