PDIA6, a member of the protein disulfide isomerase (PDI) family, functions as an oxidoreductase and isomerase, catalyzing the oxidation, reduction, and isomerization of disulfide bonds. It also acts as a molecular chaperone, preventing the accumulation of misfolded proteins under stress conditions. PDIA6 is involved in multiple cellular pathways, such as the MAP4K1/JNK signaling pathway, TGF-β pathway, and Wnt/β -catenin signaling pathway, and plays a role in various biological processes including cell growth, apoptosis, autophagy, and stress response [1,2,9].

In cancer research, loss-of-function experiments in cell lines have revealed its oncogenic properties. In non-small cell lung cancer (NSCLC), PDIA6 knockdown decreased cell proliferation and increased cisplatin-induced apoptosis, while overexpression had the opposite effects, and it regulated autophagy via the MAP4K1/JNK/c-Jun signaling pathway [1]. In endometrial cancer, PDIA6 promoted cancer progression by regulating the TGF-β pathway [2]. In prostate cancer, knocking down PDIA6 decreased cell proliferation [3]. In oral squamous cell carcinoma, PDIA6 overexpression enhanced cell growth, migration, invasion, and tumorigenesis, and promoted aerobic glycolysis [5]. In pancreatic cancer, PDIA6 knockdown impaired cell malignancies and increased sensitivity to natural killer cells, and it was associated with CSN5-regulated deubiquitination of β-catenin and PD-L1 [7]. In gastric cancer, down-regulation of PDIA6 inhibited cell proliferation and chemoresistance to cisplatin, and it regulated the Wnt/β-catenin signaling pathway [9]. In addition, in the razor clam, PDIA6 was upregulated in response to thermal stress, suggesting its role in counteracting such stress [4]. In kidney cells, depletion of PDIA6 increased ER stress, impaired primary ciliogenesis, and enhanced sensitivity to ferroptosis [6]. In insulin-producing mouse cells, shRNA silencing of PDIA6 reduced insulin production and glucose-stimulated insulin secretion by modulating the RIDD activity of IRE1 [8].

In conclusion, PDIA6 is a multifunctional protein involved in diverse biological processes. Model-based research, especially loss-of-function experiments in cell lines, has shown its significance in cancer progression, stress response, ciliogenesis, and insulin secretion. These findings suggest PDIA6 as a potential biomarker and therapeutic target in various diseases, particularly cancers.