Gpx4, also known as glutathione peroxidase 4 and originally called PHGPX (phospholipid hydroperoxide glutathione peroxidase), is a selenoprotein. It serves as the main oxidoreductase using glutathione to scavenge lipid peroxidation products, playing a crucial role in maintaining redox homeostasis [1]. There are three isoforms: cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), with distinct expression patterns during development and in adulthood. It is closely associated with ferroptosis, an iron-dependent non-apoptotic cell death pathway, and also interacts with autophagic degradation pathways [1].

Loss of Gpx4 can lead to various outcomes. In some cells, it can trigger apoptosis, necroptosis, pyroptosis, or parthanatos, mediating or accelerating developmental defects, tissue damage, and sterile inflammation [1]. Copper-induced autophagic degradation of Gpx4 promotes ferroptosis, as copper enhances Gpx4 ubiquitination and its aggregation, with TAX1BP1 acting as an autophagic receptor for its degradation [2]. Inhibition of USP8, which stabilizes Gpx4, sensitizes cancer cells to ferroptosis and enhances the effect of anti-PD-1 immunotherapy in vivo [3]. In osteoarthritis, downregulation of Gpx4 increases chondrocytes' sensitivity to oxidative stress and aggravates extracellular matrix degradation through the MAPK/NFκB pathway [4].

In conclusion, Gpx4 is a key regulator in multiple biological processes, especially in lipid oxidation and ferroptosis. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models have revealed its significant role in various diseases, including neurodegeneration, infertility, inflammation, immune disorders, ischemia-reperfusion injury, and cancer [1]. These findings provide insights into potential therapeutic strategies targeting Gpx4-related pathways for treating these diseases.

References:

1. Xie, Yangchun, Kang, Rui, Klionsky, Daniel J, Tang, Daolin. 2023. GPX4 in cell death, autophagy, and disease. In Autophagy, 19, 2621-2638. doi:10.1080/15548627.2023.2218764. https://pubmed.ncbi.nlm.nih.gov/37272058/

2. Xue, Qian, Yan, Ding, Chen, Xi, Tang, Daolin, Liu, Jinbao. 2023. Copper-dependent autophagic degradation of GPX4 drives ferroptosis. In Autophagy, 19, 1982-1996. doi:10.1080/15548627.2023.2165323. https://pubmed.ncbi.nlm.nih.gov/36622894/

3. Li, Haiou, Sun, Yishuang, Yao, Yingmeng, Song, Jiquan, Zhang, Jinfang. 2024. USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2315541121. doi:10.1073/pnas.2315541121. https://pubmed.ncbi.nlm.nih.gov/38598341/

4. Miao, Yu, Chen, Yiwei, Xue, Feng, Zhang, Changqing, Li, Guangyi. 2022. Contribution of ferroptosis and GPX4's dual functions to osteoarthritis progression. In EBioMedicine, 76, 103847. doi:10.1016/j.ebiom.2022.103847. https://pubmed.ncbi.nlm.nih.gov/35101656/