H3K18la-PSMG1 Axis in Bladder Cancer Progression: Curcumin as a Therapeutic Candidate.

Although multiple therapeutic modalities, including surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy, have improved the management of bladder cancer, the clinical outcome of muscle-invasive bladder cancer (MIBC) remains unsatisfactory. To address this challenge, we identified MIBC-related genes (MIBC.RGs) through transcriptomic and proteomic analyses and developed a prognostic model to predict patient outcomes. Among the candidate genes, PSMG1 was prioritized through an integrated framework combining machine learning-based screening and single-cell transcriptomic analysis. Experimental analyses revealed that PSMG1 was markedly upregulated in bladder cancer (BCa), progressively upregulated from normal tissue to MIBC, and PSMG1 silencing reduced cell proliferation, invasion, and clonogenic capacity in vitro, while attenuating tumor growth in vivo. Mechanistically, our data suggest that PSMG1 may promote BCa aggressiveness, at least in part, by affecting E-cadherin stability and EMT-related signaling. Epigenetic profiling revealed significant H3K18la enrichment at the PSMG1 promoter, supporting a potential H3K18la-PSMG1 regulatory axis. Finally, molecular docking, proteomic profiling, and Drug Affinity Responsive Target Stability (DARTS) assays prioritized Curcumin as a candidate compound potentially associated with PSMG1 targeting. Overall, our findings indicate that the H3K18la-PSMG1 axis may participate in BCa progression and support further evaluation of Curcumin in PSMG1-associated therapeutic strategies.