Dysregulation of the bile acid signaling network in non-alcoholic fatty liver disease: Mechanisms and a new paradigm of precision network pharmacology.

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease worldwide, characterized by complex pathogenesis and a lack of effective therapies. The bile acid (BA) "synthesis-transport-signaling" axis serves as a central hub integrating gut microbiota, host metabolism, and immunity, and its network dysregulation is a key driver of NAFLD progression. This review systematically elaborates how dysfunction of key enzymes, transporters, and receptors (e.g., farnesoid X receptor (FXR), Takeda G protein-coupled receptor 5 (TGR5)) within this axis drives hepatic steatosis, inflammation, and fibrosis by reshaping the BA pool, disrupting enterohepatic circulation, and perturbing receptor cross-talk. Current pharmacological strategies targeting single nodes are constrained by interspecies differences in BA profiles, network complexity, and off-target effects, posing significant challenges to their efficacy and safety. Consequently, we propose a paradigm shift from "single-target" approaches towards "precision network pharmacology." This entails developing novel bile acid conjugates, dual-target or multi-target agents, designing rational combination therapies, and stratifying patients based on their BA metabolic phenotypes. Guided by human-relevant models and novel biomarkers, this framework aims to systemically restore BA signaling network homeostasis and enable personalized intervention, offering a novel theoretical and translational roadmap for conquering NAFLD.