ROS-Mediated Apoptosis-Like Death Induced by Genistein in Candida albicans.

Candida albicans is an opportunistic fungal pathogen responsible for a wide spectrum of infections, and increasing antifungal resistance has intensified the need for new therapeutic strategies that operate through mechanisms distinct from membrane-targeting agents. In this study, we investigated the antifungal mechanism of genistein, a naturally occurring isoflavonoid, with particular focus on oxidative stress-mediated apoptosis-like cell death. Genistein treatment markedly elevated intracellular and mitochondrial reactive oxygen species (ROS) levels, while pretreatment with the ROS scavenger Tiron effectively suppressed ROS accumulation, indicating a ROS-dependent process. Excessive ROS generation disrupted intracellular redox balance by reducing the GSH/GSSG ratio and triggered apoptosis-associated events, including DNA fragmentation, activation of metacaspase-like proteases and phosphatidylserine externalization. These sequential responses demonstrate that oxidative stress acts as an upstream regulator initiating apoptosis-like programmed cell death in C. albicans. Collectively, our findings reveal a mechanistic model in which genistein induces controlled cell death through ROS-driven mitochondrial dysfunction and downstream apoptotic signaling, suggesting that genistein and related redox-modulating compounds may serve as promising candidates for the development of alternative antifungal therapies targeting oxidative vulnerabilities.