Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function

Wu et al. show that, upon activation by insulin-like growth factor 1 receptor and AKT, creatine kinase B exhibits a moonlighting function as protein kinase to phosphorylate glutathione peroxidase 4 to prevent its degradation, thereby suppressing ferroptosis and enhancing tumour growth in mice. Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.

Automated summary

Wu et al. found that creatine kinase B (CKB), when activated by insulin-like growth factor 1 receptor and AKT, exhibits a moonlighting function as a protein kinase, phosphorylating glutathione peroxidase 4 (GPX4) to prevent its degradation, thus suppressing ferroptosis and promoting tumor growth in mice. The study demonstrates that AKT phosphorylates CKB, leading to reduced CKB activity and increased CKB binding to GPX4. CKB then phosphorylates GPX4, preventing HSC70 binding and protecting GPX4 from degradation, thereby alleviating ferroptosis and promoting tumor growth. This study highlights the potential of targeting the protein kinase activity of CKB for cancer treatment.