Quercetin triggers iron-dependent cell death in Saccharomyces cerevisiae

Quercetin, a ubiquitous polyphenolic flavonoid, exhibits antimicrobial effects associated with apoptosis-like cell death. However, whether quercetin induces ferroptosis-like cell death, a recently recognized form of regulated cell death (RCD), in microbial cells remains unclear. To investigate its antifungal mode of action, Saccharomyces cerevisiae, a model organism with a well-characterized vacuolar iron-storage system, was used. Given the role of oxidative stress in quercetin-induced antimicrobial activity, intracellular reactive oxygen species (ROS) generation was first examined. Quercetin treatment significantly increased superoxide (O₂^-) levels and intracellular iron accumulation, thereby promoting iron redox cycling and hydroxyl radical (•OH) production. This iron-dependent oxidative stress was accompanied by glutathione (GSH) depletion, enhanced lipid peroxidation, and subsequent loss of membrane integrity. In addition, quercetin-induced oxidative stress caused alterations in mitochondrial mass and membrane potential. Despite extensive oxidative damage, no evidence of apoptosis-like cell death, including DNA fragmentation or caspase activation, was detected. In contrast, lipid ROS accumulation was evident, and several oxidative changes were alleviated by pretreatment with ferrostatin-1, a lipid ROS scavenger and ferroptosis inhibitor, before quercetin exposure. Collectively, these findings demonstrate that quercetin induces ferroptosis-like cell death in S. cerevisiae through iron-dependent oxidative damage and lipid peroxidation.