From lipid overload to autophagy collapse: how lipid dysregulation drives chronic inflammation and metabolic disease

Autophagy is a central homeostatic mechanism that preserves intracellular quality control by clearing damaged organelles, aggregated proteins, and excess lipids. Increasing evidence indicates that the lipid-autophagy axis is a critical determinant of chronic inflammatory and metabolic disease. Cholesterol-rich and oxidatively modified lipoproteins, including very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), oxidized LDL, and lipoprotein(a), can impose lysosomal stress, disturb autophagosome maturation, and amplify oxidative and inflammatory signaling, whereas high-density lipoprotein-mediated cholesterol efflux supports cellular lipid clearance and autophagic competence. When chronic lipid overload exceeds lysosomal and autophagic capacity, cells transition from adaptive lipophagy to impaired autophagic flux, leading to lipid-droplet accumulation, mitochondrial dysfunction, inflammasome activation, and sustained cytokine production. This review synthesizes mechanistic insights linking lipid dysregulation and autophagy failure across atherosclerosis, metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH), and neurocognitive disorders. We further discuss how defective autophagy impairs efferocytosis, phagosome maturation, and inflammasome restraint, thereby contributing to unresolved inflammation and inflammatory cell-death signaling. Translationally, we outline therapeutic strategies that combine metabolic unloading, lipid-lowering interventions, autophagy-lysosome modulation, and flux-based biomarker approaches.

Lipid-induced autophagic flux failure provides a unifying framework for understanding how metabolic stress evolves into chronic inflammation and organ dysfunction and identifies actionable targets for precision therapeutic intervention.