Lipid metabolism-MAFLD crosstalk: mechanisms and therapy

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disorder worldwide, encompassing a spectrum that ranges from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis. However, its precise pathogenic mechanisms remain incompletely understood, and effective, specific pharmacological treatments are still lacking. Disruption of hepatic lipid metabolic homeostasis represents a central event in the onset and progression of MAFLD. With advances in lipidomics and metabolomics, researchers can now more accurately delineate the aberrant accumulation of specific lipid species within hepatocytes and their pivotal roles in triggering insulin resistance, oxidative stress, and inflammatory responses. This review systematically summarizes the core mechanisms by which hepatic lipid metabolic dysregulation drives MAFLD progression and highlights recent advances in therapeutic strategies targeting lipotoxic pathways, metabolic reprogramming, and related molecular targets. These insights aim to provide a theoretical basis and new perspectives for future research and clinical intervention in this field.