Abstract

Trichosporon asahii is a significant pathogen of invasive fungal infections, exhibiting low susceptibility to multiple first-line antifungal drugs, which poses severe challenges in clinical treatment. This study discovered for the first time that ferrous sulfate (FeSO₄) has a potent inhibitory effect against this fungus by inducing a ferroptosis-like cell death. This process ischaracterized by non-apoptotic cell death, iron ion dependence, reactive oxygen species (ROS) burst, lipid peroxide accumulation, and damage to key membrane systems including the loss of mitochondrial membrane potential. This process can be partially reversed by the ferroptosis-specific inhibitor Ferrostatin-1, and provided a modest improvement in fungal survival. Transcriptomic analysis further revealed that FeSO₄ treatment causes significant alterations in the expression of genes related to redox processes, glutathione metabolism, and the proteasome pathway. This study, for the first time, elucidates a ferroptosis-like death pathway in Trichosporon asahii triggered by exogenous Fe 2+ , which depends on iron accumulation and lipid peroxidation, thereby revealing a novel, ferroptosis-based mechanism with potential for future antifungal development.