Abstract
Ferroptosis induction has emerged as a promising therapeutic approach for prostate cancer (PCa), either as a monotherapy or in combination with hormone therapy. Therefore, identifying the mechanisms regulating ferroptosis in PCa cells is essential. Our previous study demonstrated that HJURP, an oncogene upregulated in PCa cells, plays a role in tumor proliferation. Here, we expand these findings by elucidating a novel mechanism by which HJURP inhibits sensitivity to ferroptosis inducers in PCa cells via the PRDX1/reactive oxygen species (ROS) pathway in vitro and in vivo. Mechanistically, HJURP forms disulfide-linked intermediates with PRDX1 through Cys327 and Cys457 residues. This disulfide binding promotes PRDX1 redox cycling and inhibits its hyperoxidation. As a result, HJURP enhances the peroxidase activity of PRDX1, leading to a decrease in ROS levels and subsequently suppressing lipid peroxidation induced by ferroptosis inducers. These findings reveal the potential of HJURP/PRDX1 as novel therapeutic targets and biomarkers of ferroptosis in PCa patients.