The role of bile acid receptors in cholestatic liver disease: pathophysiological insights and therapeutic advances

INTRODUCTION: Cholestatic liver disease (CLD) is a group of hepatobiliary disorders characterized by impaired bile flow, leading to the accumulation of toxic bile acids (BAs) and progressive liver injury. The available pharmacotherapies are limited and often inadequate. AREAS COVERED: This review explores the therapeutic potential of BA-activated receptors, encompassing nuclear receptors and membrane-bound G protein-coupled receptors, in the context of CLD. A comprehensive search of the relevant literature was conducted by means of targeted searches of recent peer-reviewed studies focusing on preclinical and clinical studies of BA receptor modulators. The present study transcends a mere descriptive catalog, instead providing a balanced assessment of key signaling cascades. Moreover, the text undertakes a critical discussion of translational failures and safety concerns. The present study focuses on the examination of emerging therapeutic classes and experimental natural products, with particular emphasis on clinical feasibility and limitations. EXPERT OPINION: The failure of pan-FXR agonists signals a need for a paradigm shift. The present study puts forward a novel framework for the development of context-dependent, isoform-selective modulators. It is anticipated that a shift from pan‑FXR agonism to pathway‑selective modulation will occur within a five-year timeframe.