Gpx3, glutathione peroxidase 3, is a selenoprotein and the only extracellular GPx in a family of oxidoreductases. It catalyzes the detoxification of hydro-and soluble lipid hydroperoxides by reduced glutathione, playing a crucial role in the antioxidant defense system [2]. It is involved in maintaining redox balance, which is essential for normal cell function and is associated with multiple biological processes and diseases [2]. Genetic models, such as gene knockout models, are valuable for studying its function.

In a spontaneous metastatic model, conditional knockout of Gpx3 in alveolar type 2 (AT2) cells suppressed lung metastasis. Tumor-polarized GPX3+ AT2 cells promote premetastatic niche formation by inhibiting CD4+ T cell proliferation and enhancing regulatory T cell generation, with tumor exosome-induced Gpx3 expression stabilizing HIF-1α to promote IL-10 production [1]. In ovarian cancer, knockdown of Gpx3 in ID8 cells abrogated clonogenicity and intraperitoneal tumor development in vivo, and RNA sequencing showed decreased gene expression related to pro-tumorigenic signaling pathways. Gpx3 also regulates the expression of GDF15 [4]. In chicken cardiomyocytes, Gpx3 suppression increased ROS levels, induced apoptosis through upregulating Caspase-3, and autophagy was also promoted by inhibiting mTOR and increasing ATG-7, ATG-10, and ATG-12 expression [3]. In a murine model of pulmonary artery banding, GPx3-deficient mice had enhanced adverse right ventricular remodeling and signs of right ventricular dysfunction [5]. In chronic kidney disease models, down-regulation of Gpx3 in renal tubular epithelium orchestrated an oxidatively stressed extracellular microenvironment, promoting fibroblast activation and kidney fibrosis [6].

In conclusion, Gpx3 is crucial for maintaining redox balance. Through gene knockout-based research, it has been shown to play important roles in various disease conditions. In lung metastasis, it promotes premetastatic niche formation; in ovarian cancer, it supports tumor progression; in cardiomyocytes, it is involved in apoptosis and autophagy regulation; in right ventricular remodeling, it affects the process; and in kidney fibrosis, it impacts the extracellular microenvironment to drive fibroblast activation. These findings from knockout models contribute to understanding the mechanisms of these diseases and may provide potential therapeutic targets.

References:

1. Wang, Zixin, Zhu, Jie, Liu, Yanfang, Cao, Xuetao, Gu, Yan. 2022. Tumor-polarized GPX3+ AT2 lung epithelial cells promote premetastatic niche formation. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2201899119. doi:10.1073/pnas.2201899119. https://pubmed.ncbi.nlm.nih.gov/35914155/

2. Chang, Caroline, Worley, Beth L, Phaëton, Rébécca, Hempel, Nadine. 2020. Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer. In Cancers, 12, . doi:10.3390/cancers12082197. https://pubmed.ncbi.nlm.nih.gov/32781581/

3. Gong, Yafan, Yang, Jie, Cai, Jingzeng, Zhang, Jun Min, Zhang, Ziwei. 2018. Effect of Gpx3 gene silencing by siRNA on apoptosis and autophagy in chicken cardiomyocytes. In Journal of cellular physiology, 234, 7828-7838. doi:10.1002/jcp.27842. https://pubmed.ncbi.nlm.nih.gov/30515791/

4. Chang, Caroline, Cheng, Ya-Yun, Kamlapurkar, Shriya, Phaëton, Rébécca, Hempel, Nadine. 2024. GPX3 supports ovarian cancer tumor progression in vivo and promotes expression of GDF15. In Gynecologic oncology, 185, 8-16. doi:10.1016/j.ygyno.2024.02.004. https://pubmed.ncbi.nlm.nih.gov/38342006/

5. Covington, Taylor A, Pilz, Patrick M, Mulhern, Ryan M, Fisch, Sudeshna, Grune, Jana. 2023. GPx3 deficiency exacerbates maladaptive right ventricular remodeling in experimental pulmonary artery banding. In American journal of physiology. Lung cellular and molecular physiology, 324, L550-L556. doi:10.1152/ajplung.00379.2022. https://pubmed.ncbi.nlm.nih.gov/36880685/

6. Li, Li, Lu, Meizhi, Peng, Yiling, Zhou, Lili, Liu, Youhua. 2023. Oxidatively stressed extracellular microenvironment drives fibroblast activation and kidney fibrosis. In Redox biology, 67, 102868. doi:10.1016/j.redox.2023.102868. https://pubmed.ncbi.nlm.nih.gov/37690165/