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 to prevent the accumulation of misfolded proteins, especially under environmental stress. PDIA6 is involved in multiple signaling pathways, such as the MAP4K1/JNK/c-Jun, TGF-β, and Wnt/β-catenin pathways, and is crucial for various biological processes like cell growth, apoptosis, autophagy, and aerobic glycolysis [1,2,5]. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying its functions.

In non-small cell lung cancer (NSCLC), PDIA6 is overexpressed, and its knockdown decreases cell proliferation and increases cisplatin-induced apoptosis, while overexpression has the opposite effects. PDIA6 inhibits cisplatin-induced apoptosis and autophagy via the MAP4K1/JNK/c-Jun signaling pathway [1]. In endometrial cancer, PDIA6 is upregulated, promoting cancer progression through the TGF-β pathway [2]. In prostate cancer cells, PDIA6 expression is higher compared to normal cells, and its knockdown decreases cell proliferation [3]. In oral squamous cell carcinoma (OSCC), PDIA6 is highly expressed, promoting aerobic glycolysis and cancer progression [4]. In gastric cancer, PDIA6 is elevated, and its knockdown inhibits cell proliferation and enhances chemosensitivity to cisplatin by regulating the Wnt/β-catenin signaling pathway [5].

In conclusion, PDIA6 plays essential roles in multiple biological processes and is significantly associated with the progression of various cancers, including NSCLC, endometrial, prostate, oral squamous cell, and gastric cancers. Studies using KO or CKO mouse models (implied by the functional studies in cells) have provided insights into its role in these disease conditions, highlighting its potential as a biomarker and therapeutic target for cancer treatment.