HSPA9 contributes to tumor progression and ferroptosis resistance by enhancing USP14-driven SLC7A11 deubiquitination in multiple myeloma

Ferroptosis, a regulated cell death triggered by overload-dependent lipid peroxidation, is implicated in multiple human cancers. The mechanisms underlying ferroptosis in multiple myeloma (MM) remain enigmatic. Here, we confirmed that HSPA9 is overexpressed in MM samples and correlates with unfavorable outcomes. Functionally, HSPA9 enhances MM cell viability, ferroptosis resistance, and tumorigenicity, suggesting its oncogenic role. Proteomics screening identified SLC7A11, a key ferroptosis suppressor, as a HSPA9 interactor. Mechanistically, HSPA9 serves as a bridge to strengthen the interaction between USP14 and SLC7A11, modulating USP14-mediated SLC7A11 deubiquitination. Furthermore, the inhibition of USP14 with IU1 enhances the SLC7A11 ubiquitination and degradation, promoting ferroptosis and showing therapeutic efficacy in MM xenograft models. Clinically, HSPA9, USP14, and SLC7A11 expression are positively correlated in MM samples, which have a prognostic value. Our study reveals HSPA9-USP14-SLC7A11 axis as a key regulator of ferroptosis in MM and a potential therapeutic target.