Lipid metabolic reprogramming in osteoarthritis: cartilage-centered mechanisms, whole-joint interactions, and therapeutic challenges.

Osteoarthritis (OA) is a biologically heterogeneous whole-joint disorder characterized by cartilage damage, synovitis, subchondral bone remodeling, pain, and progressive functional decline. Although OA has long been viewed primarily as a mechanically driven disorder, clinical and experimental evidence indicates that lipid metabolic dysregulation contributes to OA susceptibility, symptom burden, and disease progression in at least a subset of patients. This review focuses on how lipid metabolic dysregulation shapes inflammatory, catabolic, and survival pathways in OA, with particular emphasis on cartilage-centered mechanisms and whole-joint metabolic interactions. We discuss cholesterol dysregulation, fatty-acid lipotoxicity, neutral lipid/lipid-droplet accumulation, phospholipid remodeling, and obesity-associated adipose-joint crosstalk as major components of metabolic OA. Key pathways linking lipid imbalance to OA pathology include the CH25H-CYP7B1-RORα axis, fatty-acid-induced lipotoxic stress, mitochondrial oxidative injury, and phospholipid peroxidation-driven ferroptosis. Under conditions of iron dyshomeostasis, lipid peroxidation can compromise chondrocyte membrane integrity and promote ferroptotic cell death, thereby amplifying matrix-destructive responses. HIF-1α signaling is context-dependent: basal or appropriately stabilized HIF-1α may support hypoxic adaptation and mitochondrial quality control, whereas lipid overload, lactate accumulation, and chronic inflammation can redirect HIF-1α toward proinflammatory metabolic amplification. We also evaluate the translational prospects and current limitations of lipid-targeted strategies, including statins, metabolic interventions, and nutritional approaches. Current evidence supports metabolic stratification in OA, but important gaps remain in linking circulating lipid alterations to tissue-specific mechanisms and in identifying patient subsets most likely to benefit from lipid-targeted intervention.