Abstract

Ferroptosis, an iron-dependent form of programmed cell death driven by toxic lipid peroxide accumulation, plays a critical role in various diseases, making its modulation a promising therapeutic strategy. In this study, we identified several L-type calcium channel blockers as novel inhibitors of ferroptosis. We further elucidated that calcium-dependent activation of PKCβ drives ferroptosis by phosphorylating two key enzymes, ACSL4 and ALOX15, at multiple sites. We generated phosphorylation-specific antibodies targeting these sites and confirmed their specificity in the context of ferroptosis. Furthermore, upon induction of ferroptosis, the ACSL4-PKCβ-ALOX15 complex relocates to lipid droplets, highlighting a critical role of lipid droplets in ferroptosis. Notably, elevated PKCβ levels enhance the efficacy of ferroptosis-inducing cancer therapies, while inhibition of the Ca 2 + -PKCβ signaling pathway protects against acute pancreatitis by suppressing ferroptosis. These findings underscore the therapeutic potential of targeting Ca 2 + -PKCβ-mediated ferroptosis, offering new avenues for the treatment of cancer and acute pancreatitis.