Hepatocyte nuclear factors dynamically regulate triglyceride metabolic reprogramming in metabolic dysfunction-associated steatotic liver disease: Mechanisms and implications

Metabolic dysfunction-associated steatotic liver disease, characterized by pathological intracellular triglyceride (TG) accumulation, is mechanistically associated with the disrupted spatiotemporal regulation of hepatocyte nuclear factor (HNF)-dependent transcriptional programs. HNFs, including key members such as HNF-1α, HNF-4α, and HNF-6, constitute a liver-enriched family of transcription factors that govern hepatic lipid metabolism through hierarchical transcriptional regulatory networks. These networks critically regulate the dynamic equilibrium of TG metabolism, encompassing TG synthesis, storage, lipolysis, and lipoprotein-mediated export. This review comprehensively deciphers the molecular cascades through which HNF dysfunction exacerbates TG metabolic disorder in metabolic dysfunction-associated steatotic liver disease. Additionally, we evaluate emerging translational strategies targeting key HNF regulatory nodes and discuss current clinical challenges as well as potential solutions.