Osteoarthritis (OA), a chronic degenerative joint disorder, is a primary cause of disability, affecting over 520 million people globally.1 While age-standardized rates (ASRs) for incidence, prevalence, and disability-adjusted life years (DALYs) are projected to decline slightly annually from 2020 to 2035, absolute case numbers will continue to rise, underscoring OA as a persistent public health challenge.2 Therefore, identification of therapeutic targets for OA is of significant clinical importance. The current research on OA drug targets is predominantly confined to blood and single-omics analysis, with a notable absence of integrated, cross-tissue, and multi-omics validation.3, 4, 5 Herein, our objective is to systematically identify tissue-specific priority drug targets for OA through a comprehensive cross-tissue and multi-omics analysis framework.