PDIA4, a member of the protein disulfide isomerases (PDI) family, catalyzes disulfide bond formation, a critical step in protein folding within the endoplasmic reticulum. It is involved in multiple pathways, such as the endoplasmic reticulum stress response, and has been implicated in various biological processes like thrombosis formation, cell apoptosis, and DNA repair. Genetic models, including gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions [2].

In renal cell carcinoma (RCC), downregulation of PDIA4 in RCC cells increased sensitivity to ferroptosis, while overexpression conferred resistance. PDIA4 promoted ferroptosis resistance via induction of ATF4/SLC7A11 signaling, and salinomycin treatment, which suppressed PDIA4, sensitized RCC to ferroptosis [1]. In glioblastoma (GBM), PDIA4 was overexpressed, and its downregulation promoted apoptosis, inhibited proliferation, and decreased aerobic glycolysis metabolites. PDIA4 regulated GBM cell proliferation and apoptosis via the PI3K/AKT/m-TOR pathway [3]. In diabetes, ablation of Pdia4 in mice alleviated diabetes, while overexpression had the opposite effect. Pdia4 regulated β-cell death, dysfunction, and ROS production, and a Pdia4 inhibitor suppressed diabetic development [4].

In summary, PDIA4 plays crucial roles in various biological processes and diseases. Model-based research, especially KO/CKO mouse models, has revealed its importance in cancer, diabetes, and other conditions. Understanding PDIA4 functions provides potential therapeutic targets for these diseases.

References:

1. Kang, Lichun, Wang, Dekun, Shen, Tianyu, Zhang, Yuying, Tan, Xiaoyue. 2023. PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma. In Cell death & disease, 14, 193. doi:10.1038/s41419-023-05719-x. https://pubmed.ncbi.nlm.nih.gov/36906674/

2. Wang, Zeyu, Zhang, Hao, Cheng, Quan. 2019. PDIA4: The basic characteristics, functions and its potential connection with cancer. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 122, 109688. doi:10.1016/j.biopha.2019.109688. https://pubmed.ncbi.nlm.nih.gov/31794946/

3. Wang, Ming, Zhang, Wenyan, Liu, Yibo, Chen, Ligang, Zhou, Jie. 2022. PDIA4 promotes glioblastoma progression via the PI3K/AKT/m-TOR pathway. In Biochemical and biophysical research communications, 597, 83-90. doi:10.1016/j.bbrc.2022.01.115. https://pubmed.ncbi.nlm.nih.gov/35131603/

4. Kuo, Tien-Fen, Hsu, Shuo-Wen, Huang, Shou-Hsien, Yang, Greta, Yang, Wen-Chin. 2021. Pdia4 regulates β-cell pathogenesis in diabetes: molecular mechanism and targeted therapy. In EMBO molecular medicine, 13, e11668. doi:10.15252/emmm.201911668. https://pubmed.ncbi.nlm.nih.gov/34542937/