Targeting USP10/SCD1 axis by RAF265 suppresses lipogenesis and induced ferroptosis in head and neck squamous cell carcinoma

Abstract Ubiquitin-specific peptidase 10 (USP10) has been implicated in the development of various cancers, including head and neck squamous cell carcinoma (HNSCC). Nevertheless, the precise mechanisms through which USP10 functions in HNSCC are not fully understood. In this work, we demonstrate that USP10 acts as a deubiquitinating enzyme for stearoyl-CoA desaturase 1 (SCD1), directly interacting with SCD1 to remove ubiquitin chains, thereby enhancing its protein stability. This stabilization results in elevated SCD1 levels and then promotes lipogenesis of monounsaturated fatty acids and reduced ferroptotic cell death in HNSCC cells. Furthermore, our data reveal that the transcription factor E2F4 activates USP10 expression by binding to its promoter region in HNSCC. Notably, we discover that RAF265, a compound already approved by the FDA, effectively inhibits USP10 activity, leading to decreased SCD1 expression and lipogenesis, which then suppresses tumor growth and enhances ferroptosis in both in vitro and in vivo models of HNSCC. Collectively, these results underscore the critical role of the E2F4/USP10/SCD1 pathway in modulating ferroptosis and driving HNSCC progression, suggesting that targeting this axis with RAF265 may offer a promising strategy for therapeutic intervention in this malignancy.