Protein kinase A regulates ferroptosis by controlling GPX4 mA modification through phosphorylation of ALKBH5.

GPX4-dependent ferroptosis has emerged as a therapeutic strategy for cancer treatment. Here, we demonstrated that protein kinase A (PKA) participates in the regulation of ferroptosis by controlling the mA modification of GPX4 in an ALKBH5-dependent manner. Notably, we identified ALKBH5, an mA demethylase, as a novel target of PKA, which drives phosphorylation-dependent degradation of ALKBH5 protein. Moreover, the deletion of ALKBH5 represses ferroptotic cell death by maintaining GPX4 mA modification and stability. Thus, by regulating ALKBH5-dependent GPX4 stability, PKA acts as a key regulator of ferroptosis. Our study unveils the involvement of PKA in mA modification, which could control GPX4-dependent ferroptosis and tumor progression.