Microsomal glutathione transferase 1: A master regulator of ferroptosis in cancer and beyond

Microsomal glutathione transferase 1 (MGST1), a membrane-associated enzyme of the MAPEG family, has emerged as a central regulator of ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxide accumulation. Traditionally recognized for its roles in detoxification and oxidative stress responses, MGST1 has recently been identified as a key suppressor of ferroptosis through multiple mechanisms, including glutathione-dependent reduction of lipid hydroperoxides, inhibition of arachidonate 5-lipoxygenase activity, modulation of iron availability through melanin-associated sequestration, and integration with transcriptional, epigenetic, post-translational, and signaling networks. This review summarizes the structural and enzymatic properties of MGST1, its subcellular localization at the endoplasmic reticulum and outer mitochondrial membrane, and its diverse regulatory mechanisms in ferroptosis control. In cancer, elevated MGST1 promotes tumor cell survival, proliferation, metastasis, immune evasion, and resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy by buffering lipid peroxidation and limiting ferroptotic death. Conversely, in non-malignant diseases, including myocardial ischemia-reperfusion injury, neurotoxicity, acute pancreatitis, intervertebral disc degeneration, diabetic cardiomyopathy, and inflammatory disorders, MGST1 may protect vulnerable tissues from ferroptosis-associated injury. These context-dependent functions create a therapeutic paradox: MGST1 inhibition may enhance cancer treatment efficacy, whereas MGST1 activation may preserve normal tissue integrity in degenerative or ischemic conditions. Emerging strategies include small-molecule inhibitors, gene interference, epigenetic modulation, NRF2-mediated activation, and combination approaches with existing therapies. MGST1 also holds promise as a diagnostic, prognostic, and treatment-stratification biomarker. Overall, MGST1 represents a pivotal ferroptosis regulator with broad translational relevance.