Succinate exacerbates obesity-associated osteoarthritis: mitochondrial dysfunction mediated by SUCNR1 activation and succinylation modification

Osteoarthritis (OA) is the most prevalent degenerative joint disease and is closely related to obesity. The molecular mechanisms underlying obesity-induced metabolic alterations that lead to cartilage degeneration have not been fully elucidated. Succinate, a key intermediate in the Krebs cycle, exhibits signaling functions that extend beyond its traditional metabolic role. This study demonstrates that succinate is significantly accumulated in the knee joint of obesity-associated OA. Succinate exacerbates obesity-associated cartilage degeneration through a combination of extracellular and intracellular pathways, which converge on mitochondrial dysfunction. Mechanistically, extracellular succinate activates G protein-coupled receptor succinate receptor-1 (SUCNR1), triggering mitochondrial fission and activation of the cGAS-STING pathway. Intracellular succinate reduces NADPH levels and promotes mitochondrial reactive oxygen species (mtROS) accumulation, in association with increased IDH2 succinylation. Additionally, sirtuin 5 (SIRT5) acts as an IDH2 desuccinylase and exerts a protective effect against intracellular succinate-induced cartilage degeneration. To target both intracellular and extracellular succinate, the phenylboronic acid-modified gelatin hydrogel is designed to load the SUCNR1 inhibitor 5 g and the SIRT5 agonist puerarin. This injectable ROS-responsive system targeting succinate exhibits remarkable therapeutic efficacy in vivo. These findings suggest that targeting succinate provides a novel therapeutic strategy for obesity-associated OA.