Pathological Copper Overload Reprograms SOD1 Activation via COMMD1 to Promote Senescence and Fibrosis

Superoxide dismutase 1 (SOD1), a copper-dependent antioxidant, is essential for redox homeostasis, and its decline drives renal senescence and fibrosis. However, the mechanisms linking profibrotic signaling to SOD1 inhibition remain unclear. Here, we identified a pathological copper-COMMD1-SOD1 axis in which intracellular copper overload paradoxically suppressed SOD1 activity. In kidney tissues from chronic kidney disease (CKD) patients and complementary in vivo and in vitro fibrotic models, we consistently observed a reduction in SOD1 activity accompanied by elevated intracellular copper levels. Lowering intracellular copper levels restored SOD1 activity, suppressed reactive oxygen species (ROS) accumulation, and alleviated cell senescence and fibrosis. Mechanistically, pathological copper overload impaired SOD1 homodimerization, the essential final step in its activation. We identified copper metabolism MURR1 domain containing 1 (COMMD1) as a key copper-sensitive mediator of this process. Copper overload acted upstream, simultaneously upregulating COMMD1 expression and enhancing its binding affinity to SOD1. This enhanced COMMD1-SOD1 interaction directly disrupted SOD1 homodimer assembly and enzymatic function. Collectively, these findings redefined the regulatory role of copper in SOD1 activity and uncovered a previously unrecognized mechanism by which pathological copper overload paradoxically suppressed SOD1 activity via COMMD1-dependent disruption of SOD1 homodimerization, providing new insight into the pathophysiology of copper dyshomeostasis-associated diseases.