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Osteoarthritis (OA) is the most prevalent musculoskeletal disorder and the leading cause of disability worldwide. As one of the fastest growing healthproblems, OA affects 54 million people in the United States and more than 300 million people globally. Despite identification of several risk factors,including aging, joint biomechanics and genetic predisposition, epidemiological studies nowadays suggest a strong correlation between obesity and OAin patients. Obese individuals are over four times more likely to develop OA with worse pain and other symptoms, compared to individuals with normalbody weight. By using unbiased comprehensive sequencing of the genome and epigenome, as well as high-throughput measurement of metabolites incombination with a murine posttraumatic OA model, we identified NFIA as a key regulator of lipid metabolism in articular chondrocytes and defined thedeleterious role of lipid metabolism in chondrocyte homeostasis and OA progression. We are currently investigating the role of NFIA inhibition (and itsassociated downstream targets) on OA progression under obesity condition.