Hypoxia drives ferroptosis resistance and immunosuppression in hepatocellular carcinoma by inducing UBASH3B-mediated glutamine metabolism reprogramming and CXCL8 expression.

Hypoxia-induced reprogramming of glutamine metabolism and ferroptosis resistance serve as pivotal factors that drive the progression of solid tumors and contribute to therapeutic resistance. However, the potential interaction between these processes remains inadequately understood. Elucidating the regulatory mechanisms linking these pathways is essential for developing effective therapies for solid tumors. This study demonstrated that HIF-1α promotes the expression of UBASH3B in hepatocellular carcinoma (HCC), resulting in ferroptosis resistance mediated by glutamine metabolism. Mechanistically, HIF-1α-driven UBASH3B dephosphorylated MYBL2 at Y15, leading to MYBL2 stabilization and a reprogramming of glutamine metabolism that modulates ferroptosis resistance. Specifically, MYBL2 augmented the transcriptional activity of SPSB4, which facilitated the K48-linked polyubiquitination and degradation of GLUD1, a key enzyme in glutamine metabolism, at residue K191. This degradation inhibited glutamine-driven oxidative phosphorylation (OXPHOS). Furthermore, UBASH3B played a crucial role in macrophage polarization and T-cell inhibition by promoting CXCL8 expression, which contributed to immunosuppression. Finally, we found that targeting UBASH3B in HCC cells using ZIF-8-Cu@siRNA@HA nanoparticles (ZCSH NPs) enhanced the efficacy of anti-PD-1 in combination with lenvatinib treatment. In summary, our study uncovers a novel interaction between hypoxia, glutamine metabolic reprogramming, and immune suppression in HCC progression, positioning UBASH3B as a promising therapeutic target for overcoming hypoxia-induced treatment resistance.