MGST1, or microsomal glutathione S-transferase 1, is a membrane-bound glutathione transferase with glutathione-dependent transferase and peroxidase activities. It can detoxify reactive intermediates like metabolic electrophile intermediates and lipophilic hydroperoxides, and is activated by oxidative stress [5]. It is involved in multiple pathways, such as the NFE2L2-related pathway, and plays a crucial role in various biological processes, including embryonic development and hematopoiesis [6].

In pancreatic ductal adenocarcinoma (PDAC), genetic depletion of MGST1 promotes ferroptosis, while its overexpression confers resistance to KRASG12D inhibitor MRTX1133 by inhibiting lipid peroxidation-induced ferroptosis. Nuclear localization and higher levels of active β-catenin contribute to higher MGST1 expression [1,2]. In glioma, MGST1 expression is increased in TMZ-resistant cells. Silencing MGST1 down-regulates the IC50 value of TMZ and facilitates ferroptosis, and the transcription factor ZNF384 positively regulates MGST1 expression to confer TMZ resistance [3]. In myocardial ischemia/reperfusion injury after heart transplantation, overexpressing MGST1 effectively alleviates myocardial infarction, inflammation, histological damage, mitochondrial damage, and inhibits ferroptosis. DNA methyltransferase 1 (DNMT1)-mediated promoter methylation negatively regulates MGST1 [4].

In summary, MGST1 is essential for development and hematopoiesis. Its dysregulation is involved in multiple diseases including cancer and heart-related diseases. Through gene-knockout or knockdown models in these disease conditions, we've learned that MGST1's role in inhibiting ferroptosis often contributes to drug resistance in cancer, while its overexpression can protect against myocardial injury, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Xu, Chungui, Lin, Weihao, Zhang, Qi, Wang, Xiaobing, Du, Chunxia. 2024. MGST1 facilitates novel KRASG12D inhibitor resistance in KRASG12D-mutated pancreatic ductal adenocarcinoma by inhibiting ferroptosis. In Molecular medicine (Cambridge, Mass.), 30, 199. doi:10.1186/s10020-024-00972-y. https://pubmed.ncbi.nlm.nih.gov/39501138/

2. Kuang, Feimei, Liu, Jiao, Xie, Yangchun, Tang, Daolin, Kang, Rui. 2021. MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells. In Cell chemical biology, 28, 765-775.e5. doi:10.1016/j.chembiol.2021.01.006. https://pubmed.ncbi.nlm.nih.gov/33539732/

3. Yan, Tengfeng, Hu, Ping, Lv, Shigang, Fang, Hua, Xiao, Bing. 2024. ZNF384 transcriptionally activated MGST1 to confer TMZ resistance of glioma cells by negatively regulating ferroptosis. In Cancer chemotherapy and pharmacology, 94, 323-336. doi:10.1007/s00280-024-04681-5. https://pubmed.ncbi.nlm.nih.gov/38824270/

4. Yang, Yang, Zhao, Changying, Li, Chenlu, Cao, Xiantong, Wu, Qifei. 2025. MGST1 overexpression ameliorates mitochondrial dysfunction and ferroptosis during myocardial ischemia/reperfusion injury after heart transplantation. In International journal of biological macromolecules, 299, 140135. doi:10.1016/j.ijbiomac.2025.140135. https://pubmed.ncbi.nlm.nih.gov/39848358/

5. Schaffert, Courtney S. . Role of MGST1 in reactive intermediate-induced injury. In World journal of gastroenterology, 17, 2552-7. doi:10.3748/wjg.v17.i20.2552. https://pubmed.ncbi.nlm.nih.gov/21633660/

6. Bräutigam, Lars, Zhang, Jie, Dreij, Kristian, Morgenstern, Ralf, Johansson, Katarina. 2018. MGST1, a GSH transferase/peroxidase essential for development and hematopoietic stem cell differentiation. In Redox biology, 17, 171-179. doi:10.1016/j.redox.2018.04.013. https://pubmed.ncbi.nlm.nih.gov/29702404/