Liquid–Liquid Phase Separation as an Emerging Regulator of Pathways Relevant to MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, and a substantial proportion of patients progress to metabolic dysfunction-associated steatohepatitis (MASH), a more severe form characterized by hepatic inflammation and fibrosis, which contributes to increased morbidity and mortality. However, the precise pathogenic mechanisms underlying MASLD remain incompletely understood. Liquid–Liquid phase separation (LLPS) mediates the assembly of membrane-less biomolecular condensates, which dynamically regulate various cellular signaling pathways. Emerging evidence links LLPS to chronic liver diseases, including MASLD and MASH. This review focuses on the regulatory roles of LLPS in key pathophysiological processes associated with MASLD and MASH, including insulin resistance, lipid metabolism, inflammation, mitochondrial dysfunction, ferroptosis, autophagy, and fibrosis, with the aim of improving our understanding of LLPS in MASLD and providing new insights for therapeutic development.