Deubiquitination of WBP11 governs OPLAH-mediated glutathione biosynthesis to suppress triple programmed cell death in prostate cancer.

Prostate cancer (PC) is one of the most common male cancers. Cancer cells are well known for their capacity to avoid programed cell death (PCD) via a variety of molecular pathways, allowing them to survive oncogenic stress and therapeutic challenges. Although oncogenic splicing factors are frequently dysregulated in tumors, their functional interplay with PCD regulatory networks in PC remains largely uncharacterized. Here, we demonstrate that WBP11 exerts a pro-tumorigenic effect by promoting PC cell proliferation, while its genetic silencing triggers concurrent induction of apoptosis, pyroptosis, and ferroptosis. Mechanistically, WBP11 directly binds to and stabilizes OPLAH mRNA, leading to elevated intracellular glutathione levels that facilitate efficient clearance of reactive oxygen species (ROS). Additionally, we demonstrate that USP13 deubiquitinates WBP11 by specifically eliminating K48-linked ubiquitin chains at lysine 626, which increases the stability of the WBP11 protein and prevents proteasomal destruction. Using a combination of in vitro functional assays, in vivo tumor models, and systematic rescue experiments, we define a previously unrecognized signaling axis, USP13-WBP11-OPLAH, that orchestrates glutathione metabolism and confers resistance to PCD, ultimately driving malignant progression of PC. Consistent with these functional findings, clinical validation reveals that USP13, WBP11, and OPLAH are significantly upregulated at the protein level in human PC tissues, and that USP13 expression positively correlates with both WBP11 and OPLAH protein abundance. Collectively, our study identifies the USP13-WBP11-OPLAH axis as a critical regulatory module linking glutathione metabolism to PCD resistance, offering promising therapeutic targets for the treatment of advanced PC.