Lipid Metabolic Reprogramming and Bioactive Lipid Signaling in MASLD: Molecular Mechanisms, Pathogenesis and Therapeutic Opportunities

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a disorder of hepatic lipid metabolic reprogramming rather than a consequence of passive triglyceride accumulation. Chronic nutrient excess, insulin resistance, adipose tissue dysfunction, and altered nutrient-sensing pathways disrupt the balance among hepatic fatty acid uptake, de novo lipogenesis, β-oxidation, lipid storage, and lipoprotein export. These changes promote the accumulation of bioactive lipid species, including saturated fatty acids, ceramides, diacylglycerols, oxidized phospholipids, and free cholesterol. Unlike triglycerides, which may serve an adaptive buffering role under conditions of preserved lipid-storage capacity, these bioactive lipids function as metabolic stress signals that impair insulin signaling, disrupt mitochondrial and endoplasmic reticulum homeostasis, activate PKC, JNK, MAPK, NF-κB, and NLRP3 pathways, and promote hepatocyte death, immune activation, and fibrogenesis. Emerging lipidomic and multi-omic approaches further demonstrate that the molecular composition and subcellular distribution of hepatic lipids may be more closely associated with disease progression than total lipid content. This review critically integrates current evidence on hepatic lipid metabolic reprogramming, lipid-mediated signaling, organelle dysfunction, fibrosis, and molecular heterogeneity in MASLD. It also evaluates the translational potential and limitations of lipidomic biomarkers and mechanism-based therapies targeting lipogenesis, nuclear receptors, ceramide metabolism, inflammatory signaling, and fibrosis. A deeper understanding of disease-specific lipid signatures and signaling networks may support molecular endotyping, mechanism-based therapeutic strategies, and precision hepatology in patients with metabolic dysfunction-associated steatohepatitis (MASH) and progressive fibrosis.