Long-chain fatty acid metabolic imbalance in MASLD: lipotoxicity, lipidomic signatures, and therapeutic implications

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), has emerged as a leading global cause of chronic liver disease, with lipid metabolic disturbance serving as a key driver of disease initiation and progression. Fatty acids are essential components of biological membranes and participate in diverse signaling and metabolic processes. The metabolic and signaling effects of fatty acids vary with their chain length, degree of unsaturation, and the lipid class in which they are incorporated. Among them, excessive long-chain fatty acid (LCFA) availability and aberrant partitioning into different lipid pools contribute substantially to hepatic lipid accumulation and lipotoxic injury during MASLD progression. This review summarizes the sources and hepatic metabolic pathways of LCFAs and discusses how their metabolic dysregulation contributes to MASLD progression. We also discuss changes in LCFA profiles during MASLD progression and compare the differential roles of various LCFA subclasses. In addition, this review summarizes the research progress on intervention strategies against MASLD based on LCFA metabolism, including dietary regulation, drugs and natural bioactive compounds. The pathways by which gut microbiota regulates LCFA metabolism and its potential role in improving MASLD are also analyzed. Current evidence regarding stage-specific, lipid-pool-specific, and longitudinal alterations in LCFA profiles in MASLD remains limited. Further elucidation of LCFA metabolic alterations in MASLD may help identify lipid-based biomarkers and therapeutic targets, thereby promoting early identification, individualized intervention, and clinical translation.