Protein kinase A regulates ferroptosis by controlling GPX4 m⁶A 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 m⁶A modification of GPX4 in an ALKBH5-dependent manner. Notably, we identified ALKBH5, an m⁶A 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 m⁶A 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 m⁶A modification, which could control GPX4-dependent ferroptosis and tumor progression.