Synergistic Regulation of Mammary Gland Ferroptosis by Vitamin E and Selenium Under Environmental Heat Stress

Heat stress, driven by rising global temperatures and intensified by climate change, impairs mammary function by triggering oxidative damage and ferroptosis, an iron‐dependent form of cell death associated with lipid peroxidation. In this study, we combined in vitro HC11 mammary epithelial cell assays with an in vivo mouse model to define how heat stress activates ferroptosis and disrupts milk synthesis. Heat exposure reduced glutathione (GSH) levels, elevated malondialdehyde (MDA) and iron accumulation, and altered key ferroptosis markers, leading to suppressed lipid droplet formation, triglyceride content, and mTORC1‐driven protein synthesis. Direct induction of ferroptosis with RSL3 recapitulated these defects, confirming its central role in heat‐induced dysfunction. We next evaluated two dietary antioxidants, vitamin E and sodium selenite, both individually and in combination. Each nutrient individually restored redox balance, normalized ferroptosis markers, and rescued milk lipid and protein production in both models. Critically, co‐administration of vitamin E with sodium selenite produced the greatest benefit, reversing oxidative stress, ferroptotic signaling, and functional impairment to near‐control levels. These results highlight ferroptosis as a key mediator of heat stress‐induced cellular injury in mammary tissue and demonstrate that combined vitamin E and selenium supplementation exerts a synergistic protective effect.