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.

受体蛋白激酶的激活在各种癌症中普遍存在，但对铁死亡的影响尚不清楚。在这里，我们证明了胰岛素样生长因子 1 受体信号传导激活的 AKT 会磷酸化肌酸激酶 B (CKB) T133，降低 CKB 的代谢活性并增加 CKB 与谷胱甘肽过氧化物酶 4 (GPX4) 的结合。重要的是，CKB 充当蛋白激酶并使 GPX4 S104 磷酸化。这种磷酸化可阻止 HSC70 与 GPX4 结合，从而消除伴侣介导的自噬调节的 GPX4 降解，减轻铁死亡并促进小鼠肿瘤生长。此外，人肝细胞癌标本中GPX4的水平与CKB T133和GPX4 S104的磷酸化水平呈正相关，并与肝细胞癌患者的不良预后相关。