Hesperetin Induces Ferroptosis-Like Response in <i>Saccharomyces cerevisiae</i>

Hesperetin has been reported to exhibit multiple beneficial activities, including anti-inflammatory and antimicrobial effects. It has also been shown to induce intracellular reactive oxygen species (ROS). However, its mode of action in fungi remains unclear. Therefore, this study aimed to clarify the underlying mechanisms of hesperetin using <i>Saccharomyces cerevisiae</i> as a model organism. Many antimicrobial compounds exert their effects by inducing oxidative damage in microbial cells. In this study, hesperetin increased intracellular reactive oxygen species in <i>S. cerevisiae</i>. This ROS accumulation was accompanied by glutathione depletion, indicating impaired antioxidant capacity and disrupted redox balance. Increased oxidative stress was also associated with an expanded pool of reactive iron, which can drive iron-dependent chemistry to generate highly reactive hydroxyl radicals. These radicals can initiate lipid peroxidation, leading to the accumulation of lipid hydroperoxides. Notably, these oxidative and lipid damage phenotypes were suppressed by ferrostatin-1, a ferroptosis inhibitor. In addition, apoptosis-associated hallmarks, including caspase activation and DNA fragmentation, were not observed under the same conditions. These findings indicate that hesperetin induces ferroptosis-like responses in <i>S. cerevisiae</i>, providing mechanistic insight into its antifungal effects.