Oxysterol undersulfation promotes osteoarthritis by fueling chondrocyte lipid accumulation

Osteoarthritis (OA) is a common degenerative joint disease with no curative treatments and a poorly understood etiology. Here, we report that defective sulfation, a largely underexplored chemical modification of lipid metabolites, drives pathogenic lipid accumulation in chondrocytes to promote OA. Intrigued by observations of lipid droplet accumulation in cartilage from genetically modified male mice with sulfation defects, we identified that the production and sulfation status of 25-hydroxycholesterol (25HC), an oxysterol metabolite, could impact OA risk and development. Transcriptomics and peptide-centric local stability assays revealed that 25HC and its sulfated derivative (25HC3S) exhibited opposing regulatory effects on lipid biosynthesis genes and distinct protein interaction profiles. Mechanistically, 25HC activated Liver X Receptor (LXR) ligand-dependently to potentiate lipid synthesis and uptake, while 25HC3S deactivated LXR by altering its nuclear localization and promoting nucleolar sequestration, thus mitigating chondrocyte lipid accumulation and cartilage damage. Moreover, human studies linked genetic variants in 25HC sulfation pathways to OA risk, with concomitantly reduced sulfation gene expression and increased lipid accumulation in OA cartilage. These findings support an oxysterol undersulfation model wherein defective oxysterol sulfation unleashes nuclear oxysterol receptor activation to drive pathogenic chondrocyte lipid accumulation, and highlight the therapeutic potential of 25HC3S against OA.