MG53 suppresses the progression of bladder cancer through E3 ubiquitin ligase-mediated degradation of AMPKα.

MG53/TRIM72 is a member of the tripartite motif family of E3 ubiquitin ligases that regulates metabolic homeostasis and tumor-associated signaling; however, its role in bladder cancer remains undefined. We investigated the expression, function, and molecular mechanism of MG53 in bladder cancer. MG53 expression was analyzed in bladder cancer tissues and cell lines. Functional assays including proliferation, invasion, glycolytic metabolism, intracellular reactive oxygen species (ROS) accumulation, and apoptosis were performed. The interaction between MG53 and AMPKα was examined using co-immunoprecipitation and ubiquitination assays. In vivo tumor growth was assessed in xenograft models. MG53 was significantly downregulated in bladder cancer tissues compared to adjacent normal tissues, and its expression was inversely correlated with AMPKα levels. Overexpression of MG53 suppressed cell proliferation, invasion, and glycolytic metabolism, and was also accompanied by increased intracellular ROS accumulation and a higher apoptotic rate, together with elevated cleaved caspase-3 and an increased Bax/Bcl-2 ratio, in bladder cancer cells. Mechanistically, MG53 promoted the ubiquitination and proteasomal degradation of AMPKα. In vivo experiments demonstrated that MG53 overexpression inhibited tumor growth in xenograft models. Our findings reveal that MG53 functions as a tumor suppressor in bladder cancer by promoting AMPKα degradation through its E3 ubiquitin ligase activity, thereby attenuating the Warburg effect; MG53 overexpression was also associated with intracellular ROS accumulation and apoptosis in bladder cancer cells. MG53 represents a candidate therapeutic target for bladder cancer treatment, whose translational value remains to be established in future preclinical and clinical studies.