Inhibition of Calcium‐Dependent Lipid Droplets Relocation of ACSL4‐PKCβ‐ALOX15 Complex Alleviates Ferroptosis and Acute Pancreatitis

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.