PABPC1 dictates castration sensitivity in prostate cancer via orchestrating ferroptosis resistance and CD8(+) T-cell...

Resistance to next-generation androgen receptor antagonists represents a major clinical challenge in prostate cancer (PCa), underscoring the need to define its underlying mechanisms. Here, through an integrated analysis of multiple cohorts, we identify PABPC1 as an RNA-binding protein upregulated in therapy-resistant tumors, whose expression correlates with adverse clinicopathological features. Elevated PABPC1 confers enzalutamide (Enz) resistance by suppressing tumor-cell ferroptosis and CD8⁺ T-cell cytotoxicity. Mechanistically, PABPC1 promotes the cytoplasmic colocalization of EIF4A1 with ATF4 mRNA and enhances EIF4A1-associated translation of ATF4 mRNA. Subsequently, ATF4 binds the BCAT1 promoter and transcriptionally upregulates BCAT1, thereby promoting branched-chain amino acid (BCAA) metabolic remodeling and ferroptosis resistance, with leucine emerging as a major functional contributor to both ferroptosis regulation and CD8⁺ T-cell effector responses. In preclinical models, ixazomib restores ferroptotic vulnerability, reinvigorates T-cell activity, and synergizes with Enz, without overt histopathological abnormalities in major organs. These results identify the PABPC1-ATF4-BCAT1 axis as a key regulatory pathway linking RNA regulation with metabolic and immune reprogramming to facilitate treatment resistance in PCa.