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Although the copper metabolism MURR1 domain (COMMD) protein family has been associated with oncogenesis, its functional relevance in SKCM is undefined. In this study, we identified COMMD4 as a prognostic biomarker of SKCM and showed that it is positively correlated with the adverse clinical outcomes of patients. COMMD4 gene knockout (COMMD4\u2010KO) impaired the proliferative, migratory, and invasive capacities of SKCM cells\u00a0in vitro\u00a0and suppressed xenograft tumor growth\u00a0in vivo. Mechanistically, COMMD4\u2010KO induced G2\/M phase arrest by disrupting p21\u2010CDK1\u2010cyclinB1 and impeded epithelial\u2010mesenchymal transition (EMT) by reversing the E\/N cadherin switch. We also demonstrate that COMMD4 activates PI3K\u2010AKT signaling by binding PI3K\u2010p85 to release PI3K\u2010p110, thereby driving G2\/M transition and EMT. Reactivation of PI3K\u2010AKT signaling in COMMD4\u2010KO cells rescued oncogenic phenotypes. By integrative\u00a0Connectivity Map\u00a0analysis and functional validation, we identified triamterene as a pharmacological inhibitor targeting the COMMD4\u2010PI3K\u2010AKT axis, which suppressed the progression of SKCM effectively\u00a0in vitro and vivo. Our findings establish the COMMD4\u2010PI3K\u2010AKT axis as a novel and critical regulator of SKCM progression and repurpose triamterene as a promising therapeutic agent against SKCM.<\/jats:p>","DOI":"10.1111\/nyas.70141","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T15:44:26Z","timestamp":1763999066000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["COMMD4 Drives Skin Cutaneous Melanoma Progression by Targeting PI3K\u2010p85 to Activate PI3K\u2010AKT"],"prefix":"10.1111","volume":"1555","author":[{"given":"Xiaoqiang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery, The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"},{"name":"Department of Plastic Surgery, Southwest Hospital, Third Military Medical University (Army Medical University) National Key Laboratory of Trauma and Chemical Poisoning  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