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

Abstract

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.

Keywords: Hepatocyte nuclear factors; Metabolic dysfunction-associated steatotic liver disease; Triglyceride metabolic imbalance; Dynamic dysregulation of transcriptional networks; Clinical translation

Core Tip: Abnormal hepatic triglyceride deposition is the hallmark of metabolic dysfunction-associated steatotic liver disease. While this process may originate either as a hepatic manifestation of systemic metabolic dysfunction or direct local hepatic lipid metabolic imbalance, the two pathways dynamically interact to drive disease progression. Hepatocyte nuclear factors (HNFs) regulate hepatic triglyceride metabolism via transcriptional networks, and their dysfunction constitutes a key driver of metabolic dysfunction-associated steatotic liver disease pathogenesis. Targeting critical nodes in HNF regulatory networks presents new opportunities for precision therapy. This review systematically analyzes the clinical challenges involved in HNF-targeted therapies and explores potential solutions.