USP38 regulates autophagy-dependent ferroptosis by deubiquitinating CTNNB1 in melanoma

The incidence of melanoma continues to rise gradually, and its clinical management remains challenging. Ubiquitin-specific protease 38 (USP38) regulates tumor progression in multiple cancers, but its mechanism in melanoma remains elusive. We discovered USP38 overexpression in human melanoma tissues. USP38 overexpression promoted melanoma cell proliferation, migration, and epithelial-mesenchymal transition while suppressing ferroptosis. Conversely, USP38 knockdown inhibited cell growth and activated ferroptosis. USP38 knockdown triggered autophagosome formation and activated autophagy, promoting ferroptosis. Critically, inhibiting autophagy blocked USP38 knockdown-driven ferroptosis, while Erastin reversed USP38-mediated autophagosomes reduction, demonstrating autophagy-dependent ferroptosis regulation. Mechanistically, USP38 bound to Catenin Beta 1 (CTNNB1) and removed K48-linked ubiquitination, stabilizing CTNNB1 expression. In vivo and in vitro experiments demonstrated that CTNNB1 knockdown reversed USP38-driven tumor progression. Combined USP38 knockdown and CTNNB1 degrader NF764 synergistically suppressed tumor growth and induced ferroptosis. In summary, USP38 drives autophagy-dependent ferroptosis through CTNNB1 stabilization in melanoma. Targeting the USP38-CTNNB1 axis represents a promising therapeutic strategy.