Restoring metabolic flexibility: targeting organelle interaction networks in the pathogenesis and therapy of MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex and heterogeneous metabolic disorder where subcellular organelle dysfunction and disrupted inter-organelle communication are recognized as increasingly important drivers of pathogenesis, moving beyond traditional views focused solely on macroscopic metabolic regulation. This review systematically explores the functional impairments of key organelles-including mitochondria, the endoplasmic reticulum, lipid droplets, and autophagic pathways-to delineate their collective roles in fostering lipid metabolism imbalance, oxidative stress, and inflammation. A key innovation discussed is how the pathological dysregulation of membrane contact sites (MCSs) acts as a pivotal mechanism decoupling organelle function and accelerating disease progression. We conclude that therapeutic strategies aimed at restoring cellular metabolic flexibility-by precisely modulating MCSs, activating clearance pathways, and restoring energy metabolism-represent a promising new paradigm for treating MASLD, particularly in patient populations unresponsive to current therapies.