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Nevertheless, the underlying molecular mechanisms involved in melanoma metastasis are not yet entirely understood. Here, we identified ubiquitin\u2010specific protease 22 (USP22) as a pro\u2010oncogenic protein in melanoma through screening the survival profiles of 52 ubiquitin\u2010specific proteases (USPs). USP22 demonstrates a strong association with poor clinical outcomes and is significantly overexpressed in melanoma. Ablation of USP22 expression remarkably attenuates melanoma migration, invasion, and epithelial\u2013mesenchymal transition in vitro and suppresses melanoma metastasis in vivo. Mechanistically, USP22 controls melanoma metastasis through the SIRT1\/PTEN\/PI3K pathway. In addition, we conducted an United States Food and Drug Administration\u2010approved drug library screening and identified topotecan as a clinically applicable USP22\u2010targeting molecule by promoting proteasomal degradation of USP22. Finally, we found that both pharmacological and genetic silence of USP22 sensitize RSL3\u2010induced ferroptosis through suppressing the PI3K\/Akt\/mTOR pathway and its downstream SCD, and ferroptosis inhibitor could partly rescued the decreased lung metastasis by topotecan in vivo. Overall, our findings reveal a prometastatic role of USP22 and identify topotecan as a potent USP22\u2010targeting drug to limit melanoma metastasis.<\/jats:p>","DOI":"10.1002\/mco2.684","type":"journal-article","created":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T14:35:36Z","timestamp":1723473336000},"source":"Crossref","is-referenced-by-count":21,"title":["Ubiquitin\u2010specific protease 22 controls melanoma metastasis and vulnerability to ferroptosis through targeting SIRT1\/PTEN\/PI3K signaling"],"prefix":"10.1002","volume":"5","author":[{"given":"Huiyan","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Dermatology Xiangya Hospital Central South University  Changsha China"},{"name":"National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology  Changsha China"},{"name":"Furong Laboratory  Changsha China"},{"name":"Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and 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