LECT2 deficiency contributes to bile acid metabolic reprogramming and cholestatic liver injury

Background: Cholestatic liver injury involves impaired bile acid (BA) formation or flow, leading to toxic hepatic BA accumulation, yet the underlying mechanisms remain poorly understood. Leukocyte cell-derived chemotaxin 2 (LECT2) has been implicated in liver metabolic disorders; however, its specific role in cholestasis remains incompletely understood. Methods: ANIT was administered to wild-type (WT) and LECT2 knockout (KO) mice to establish an intrahepatic cholestasis model. Metabolomics and metagenomics were performed to discover the role of BA metabolism and the gut–liver axis in cholestatic liver injury. Clinical samples were analyzed to assess the relationship between LECT2 and cholestatic liver injury. Results: LECT2 deletion was associated with altered BA synthesis, characterized by a shift toward the classical pathway with upregulation of CYP7A1 and CYP8B1. Under cholestatic conditions, LECT2 deficiency was associated with aggravated liver injury, accompanied by alterations in gut microbiota composition, changes in intestinal FXR–FGF15 signaling, and increased hepatic JNK activation. In KO mice, HDCA supplementation restored the alternative synthesis pathway, FMT reshaped gut microbiota, and antibiotic cocktail treatment suppressed intestinal FXR signaling, each of which was associated with improved cholestatic liver injury. In clinical samples, LECT2 levels were negatively correlated with markers of cholestasis, supporting its potential relevance to disease severity. Conclusion: LECT2 deficiency is associated with aggravated cholestatic liver injury, which may involve altered BA synthesis, gut microbiota dysbiosis, and modulation of intestinal FXR–hepatic JNK signaling. These findings offer new insights into the role of LECT2 in regulating metabolism and identify potential therapeutic targets for managing cholestatic liver injury.