PDIA4, a member of the protein disulfide Isomerases (PDI) family, catalyzes disulfide bond formation, a crucial step in protein folding within the endoplasmic reticulum. It can adjust αIIβ3 affinities, activate platelets, and promote thrombosis formation. Also, it is involved in endoplasmic reticulum response when abnormal folding proteins accumulate [2].

In renal cell carcinoma (RCC), downregulation of PDIA4 increases sensitivity to ferroptosis, while its overexpression confers ferroptosis resistance. This is achieved through the regulation of activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 [1].

In glioblastoma, downregulation of PDIA4 promotes apoptosis, inhibits proliferation, and decreases aerobic glycolysis metabolites by inhibiting the PI3K/AKT/m-TOR pathway [3].

In diabetes, ablation of Pdia4 in mice alleviates diabetes, reduces islet destruction, blood glucose, HbA1c, and reactive oxygen species (ROS), and increases insulin secretion [4].

In summary, PDIA4 is significantly involved in multiple biological processes and disease conditions. Studies using gene knockout or knockdown models in RCC, glioblastoma, and diabetes have revealed its role in ferroptosis resistance, tumor progression, and β-cell pathogenesis, respectively. These findings suggest PDIA4 could be a potential therapeutic target in these disease areas.