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

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.

ACSL4; ALOX15; PKCβ; acute pancreatitis; calcium; ferroptosis; lipid droplets.