Role of CIRP in glioma Progression: Inhibition of ferroptosis via UBR5-Mediated ACSL4 degradation

Glioma represents the most aggressive form of primary brain tumor, characterized by restricted therapeutic strategies and unfavorable survival rates. Accumulating studies indicate that Ferroptosis is critically involved in the advancement of glioma. Although cold-inducible RNA-binding protein (CIRP), an RNA chaperone protein, upregulated in various malignancies, has not been thoroughly investigated in glioma. This research revealed that CIRP is a significantly upregulated gene in glioma patients, with high expression correlating with worse prognosis. Through functional experiments, we demonstrated that CIRP enhances proliferative, migratory, and invasive capacities of glioma cells. Notably, we discovered that CIRP enhanced GBM cell resistance to Ferroptosis, as evidenced by reduced intracellular iron levels, decreased lipid peroxidation, and elevated antioxidant capacity. Mechanistic studies revealed that CIRP facilitated the interaction between the E3 ubiquitin Ligase UBR5 and ACSL4, leading to increased ubiquitination and subsequent proteasomal degradation of ACSL4. In summary, our findings indicate that CIRP advances glioma progression via inhibiting Ferroptosis through the promotion of UBR5-mediated ACSL4 degradation.