{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T03:44:37Z","timestamp":1793418277677,"version":"4.5.0"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>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-ROR\u03b1 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-1\u03b1 signaling is context-dependent: basal or appropriately stabilized HIF-1\u03b1 may support hypoxic adaptation and mitochondrial quality control, whereas lipid overload, lactate accumulation, and chronic inflammation can redirect HIF-1\u03b1 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.<\/jats:p>","DOI":"10.3389\/fendo.2026.1825725","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T04:25:43Z","timestamp":1782707143000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Lipid metabolic reprogramming in osteoarthritis: cartilage-centered mechanisms, whole-joint interactions, and therapeutic challenges"],"prefix":"10.3389","volume":"17","author":[{"given":"Kai","family":"Xu","sequence":"first","affiliation":[{"name":"Heilongjiang University of Chinese Medicine","place":["Harbin, 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