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However, the mechanisms linking profibrotic signaling to SOD1 inhibition remain unclear. Here, we identified a pathological copper\u2010COMMD1\u2010SOD1 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.\u00a0Lowering 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\u2010sensitive mediator of this process. Copper overload acted upstream, simultaneously upregulating COMMD1 expression and enhancing its binding affinity to SOD1. This enhanced COMMD1\u2010SOD1 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\u2010dependent disruption of SOD1 homodimerization, providing new insight into the pathophysiology of copper dyshomeostasis\u2010associated diseases.<\/jats:p>","DOI":"10.1002\/advs.76391","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T16:29:47Z","timestamp":1783009787000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pathological Copper Overload Reprograms SOD1 Activation via COMMD1 to Promote Senescence and Fibrosis"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuqing","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Nephrology Tongji Hospital School of Medicine, Tongji University  Shanghai 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