Osteoarthritis (OA) is characterized by progressive cartilage degradation and chondrocyte apoptosis, yet the regulatory mechanisms remain incompletely understood. Here, we identified lysine succinylation and its dynamic modulation by the desuccinylase sirtuin 5 (SIRT5) and the succinyltransferase carnitine palmitoyltransferase 1A (CPT1A) as critical regulators of OA progression. Inflammatory stimulation suppressed global succinylation levels in chondrocytes, accompanied by decreased CPT1A and increased SIRT5 expression. In vitro, CPT1A knockdown exacerbated extracellular matrix (ECM) degradation and apoptosis, whereas silencing SIRT5 restored succinylation and protected cartilage matrix integrity. Consistently, in vivo intra-articular knockdown of CPT1A promoted OA progression, while SIRT5 knockdown alleviated cartilage damage. Proteomic analysis identified polyadenylate-binding protein 1 (PABP1) as a key succinylated effector, with succinylation at lysine 208 essential for attenuating ECM catabolism and apoptosis. Mechanistically, succinylated PABP1 competitively bound IKKβ, displacing TGF-β activated kinase 1 (TAK1) and inhibiting NFκB signaling activation. Furthermore, we identified tiotropium via high-throughput screening as a pharmacological agent that enhances PABP1 succinylation, thereby suppressing ECM degradation and chondrocyte apoptosis both in vitro and in vivo. Population-based data from the UK Biobank indicated that tiotropium use was associated with a significantly lower risk of OA development and joint replacement. Collectively, our findings reveal a novel SIRT5/CPT1A-PABP1 succinylation axis that controls OA pathogenesis via NFκB signaling, highlighting tiotropium as a promising therapeutic candidate for OA intervention.