Disulfiram attenuates immobilization-induced knee joint contracture by suppressing Caspase-1/GSDMD-mediated pyroptosis.

Joint contracture resulting from prolonged immobilization is a common complication characterized by pain, stiffness, and limited mobility. Although inflammation and tissue remodeling are known contributors, the underlying cellular mechanisms remain unclear. Here, we investigated the involvement of Caspase-1/GSDMD-mediated pyroptosis in immobilization-induced knee joint contracture and evaluated the therapeutic potential of disulfiram (DSF), an FDA-approved drug repurposed here based on its reported anti-pyroptotic activity. In a rat model of knee immobilization, we assessed joint mobility, histopathological changes, and molecular markers associated with pyroptosis. Immobilization significantly induced contracture, inflammatory infiltration, and activation of the Caspase-1/GSDMD pathway in the joint capsule. Treatment with DSF improved joint range of motion, reduced tissue damage, and reduced caspase-1/GSDMD-related pyroptosis markers and GSDMD cleavage. Notably, DSF decreased IL-1β and IL-18 protein levels without affecting their mRNA expression. Together, these findings support a role for Caspase-1/GSDMD-associated pyroptosis in immobilization-induced joint contracture and suggest that DSF alleviates contracture, at least in part, by modulating this pathway, providing new mechanistic insight and a potential therapeutic approach for preventing post-immobilization joint contracture.