Polydatin Allosterically Inhibits CAPS-Mediated Vesicular Trafficking to Reverse Inflammatory Dyshomeostasis and ECM Destabilization in Osteoarthritis

Background The irreversible homeostatic destabilization of the extracellular matrix (ECM) constitutes the fundamental pathological hallmark of osteoarthritis (OA), yet the molecular governance of the chondrocyte secretome remains largely enigmatic. Methods In this study, we integrated multi-omic bioinformatics and single-cell RNA sequencing to identify Calcium-Dependent Secretion Activator (CAPS) as a pivotal hub regulator of OA pathogenesis. To intercept CAPS-driven progression, the binding kinetics and conformational thermodynamics of the CAPS–polydatin complex were characterized through 100-ns molecular dynamics (MD) simulations. Results Our findings reveal that CAPS is aberrantly overexpressed in OA-associated inflammatory chondrocyte subsets, functioning as a critical mechanosecretory gatekeeper that orchestrates the calcium-triggered exocytosis of catabolic proteinases. MD simulations demonstrated that polydatin precisely occupies the N-terminal allosteric pocket of CAPS, effectively stabilizing its proteostasis and antagonizing the pathological docking and fusion of dense-core vesicles (DCVs) to intercept the hypersecretion of ADAMTS5 and IL-6. Crucially, polydatin-mediated CAPS inhibition reactivates the PI3K-Akt/SOX9 axis, inducing a phenotypic switch from catabolic remodeling to anabolic ECM restoration characterized by robust COL2A1 upregulation. In vivo, intra-articular administration of polydatin in DMM-induced OA models demonstrated potent disease-modifying effects (DMOAD), significantly arresting anatomical deterioration and suppressing pro-inflammatory storms. Conclusion Collectively, this investigation deciphers a previously unrecognized mechanosecretory pathway centered on CAPS and establishes the allosteric modulation of vesicular trafficking as a high-precision strategy for ECM structural re-equilibration and OA therapy.