Delavinone elicits oxidative stress and triggers ferroptosis in colorectal cancer by inhibiting PKCδ-mediated phosphorylation of Nrf2

Abstract

Ferroptosis is a potential therapeutic approach for colorectal cancer (CRC). Studies have shown that peimine and its analogs exhibit anti-cancer potential; however, the intricate relationship between ferroptosis and their efficacy in fighting CRC remains unclear. In this study, we attempted to assess the therapeutic impact of peimine and its analogs on CRC and unravel the underlying mechanisms. CRC cells and a DSS/AOM-induced CRC mouse model were employed for in vitro and in vivo experiments, molecular interactions and co-immunoprecipitation were used to identify target proteins. Among the compounds, delavinone significantly inhibited CRC cell proliferation and increased cellular lipid ROS levels, MDA accumulation, and GSH depletion; the ferroptosis inhibitors DFO and Fer-1 ameliorated delavinone-induced cell death. Mechanistically, delavinone impedes PKCδ-mediated Nrf2 phosphorylation by inhibiting the kinase activity of PKCδ, thereby decreasing Nrf2 nuclear translocation and downstream GSH synthesis-related gene expression. overexpression of GPX4 weakened the anticancer effect of delavinone, underscoring delavinone's inhibition of the PKCδ/Nrf2/GPX4 signaling axis and induction of ferroptosis in CRC cells. Consistent with in vitro findings, delavinone notably hindered AOM/DSS-induced colorectal carcinogenesis, exhibiting a pronounced pro-ferroptosis effect on CRC. This study delineates that delavinone exerts its anticancer activity by inducing ferroptosis through PKCδ inhibition, consequently reducing Nrf2 phosphorylation. These findings position delavinone as a promising candidate for CRC treatment.