PPZ1-TORC1 pathway mediates ferroptosis and antifungal resistance in Candida albicans

Candida albicans (C. albicans), a common fungal pathogen, is responsible for infections such as oral candidiasis. Given the widespread misuse of antifungal medications and the increasing resistance, it is critical to explore new strategies to eradicate C. albicans. This study investigates ferroptosis, a form of cell death previously underexplored in fungi, focusing on the role of the fungus-specific protein phosphatase Z1 (PPZ1) in regulating the target of rapamycin complex 1 (TORC1) pathway during tert-butyl hydroperoxide (t-BuOOH)-induced ferroptosis. We demonstrated that ferroptosis induced by t-BuOOH promoted the accumulation of iron-dependent lipid peroxides, leading to the death of C. albicans. Furthermore, PPZ1 deletion impairs TORC1 signaling, activates autophagy, increases sensitivity to ferroptosis following t-BuOOH exposure, and reduces resistance to various antifungal drugs. These findings reveal the role of the PPZ1-TORC1 pathway in ferroptosis and provide a theoretical basis for developing ferroptosis as a novel antifungal strategy to eradicate C. albicans. The potential combined application of ferroptosis and antifungal drugs is expected to improve the efficacy of treating fungal infections.