Nuclear receptors: pathophysiological mechanisms and drug targets in liver disease

Nuclear receptors (NRs) are ligand-dependent transcription factors required for liver development and function. As a consequence, NRs have emerged as attractive drug targets in a wide range of liver diseases. However, liver dysfunction and failure are linked to loss of hepatocyte identity characterised by deficient NR expression and activities. This might at least partly explain why several pharmacological NR modulators have proven insufficiently efficient to improve liver functionality in advanced stages of diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). In this perspective, we review the most recent advances in the hepatic NR field and discuss the contribution of multiomic approaches to our understanding of their role in the molecular organisation of an intricated transcriptional regulatory network, as well as in liver intercellular dialogues and interorgan cross-talks. We discuss the potential benefit of novel therapeutic approaches simultaneously targeting multiple NRs, which would not only reactivate the hepatic NR network and restore hepatocyte identity but also impact intercellular and interorgan interplays whose importance to control liver functions is further defined. Finally, we highlight the need of considering individual parameters such as sex and disease stage in the development of NR-based clinical strategies.