PDIA5 is a protein disulfide isomerase localized to the endoplasmic reticulum (ER) that catalyzes disulfide bond formation and rearrangement in client proteins 1. As an ER-resident chaperone, PDIA5 facilitates protein folding and maintains proteostasis in cells with high protein synthesis demands 1. Mechanistically, PDIA5 regulates protein stability through its catalytic CXXC motif-mediated disulfide bond modifications 2. In cancer cells, PDIA5 mediates androgen receptor (AR) stability by forming critical disulfide bonds in the AR ligand-binding domain, establishing a feedback loop with AR signaling 1. PDIA5 also facilitates ATF6α activation during ER stress by promoting disulfide rearrangement and ER export, enabling chemoresistance pathways 3. PDIA5 is significantly upregulated across multiple malignancies including prostate cancer, glioblastoma, and pancreatic neuroendocrine neoplasms, correlating with poor prognosis 2 4 5. High PDIA5 expression associates with increased immune infiltration and M2 macrophage accumulation, promoting tumor progression 5 6. PDIA5 inhibition sensitizes cancer cells to therapeutics and enhances immunotherapy response 1 6. In non-cancer contexts, PDIA5 expression is regulated by sex hormones and influences endometrial receptivity 7. A PDIA5 polymorphism showed no association with primary open-angle glaucoma 8.