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Published on: March 15, 2024
Ferrous sulfate induces ferroptosis-like cell death in Trichosporon asahii
Lingzhi Xu1,2, Haochen Guo1,2, Xin Yang2
1Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
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 Fe2+, which depends on iron accumulation and lipid peroxidation, thereby revealing a novel, ferroptosis-based mechanism with potential for future antifungal development.
Insights
Ferrous sulfate (FeSO₄) effectively inhibits Trichosporon asahii by inducing ferroptosis-like cell death. This novel mechanism involves iron accumulation and lipid peroxidation, offering a new avenue for antifungal drug development.
Area of Science:
- Mycology
- Pathogen Research
- Cell Death Mechanisms
Background:
- Trichosporon asahii is a major cause of invasive fungal infections.
- This pathogen shows resistance to common antifungal drugs, complicating treatment.
Purpose of the Study:
- To investigate the antifungal effects of ferrous sulfate (FeSO₄) against Trichosporon asahii.
- To elucidate the cell death pathway induced by FeSO₄ in this fungus.
Main Methods:
- Treatment of Trichosporon asahii with ferrous sulfate (FeSO₄).
- Analysis of cell death characteristics including apoptosis, iron dependence, reactive oxygen species (ROS), and lipid peroxidation.
- Assessment of mitochondrial membrane potential.
- Reversal studies using the ferroptosis inhibitor Ferrostatin-1.
- Transcriptomic analysis to identify affected gene pathways.
Main Results:
- FeSO₄ demonstrated potent inhibition of Trichosporon asahii.
- FeSO₄ induced a ferroptosis-like cell death, characterized by non-apoptotic death, iron dependence, ROS burst, and lipid peroxidation.
- Mitochondrial membrane potential was damaged.
- Ferrostatin-1 partially reversed the cell death, confirming ferroptosis involvement.
- Transcriptomic analysis revealed alterations in redox, glutathione metabolism, and proteasome pathways.
Conclusions:
- Ferrous sulfate triggers a novel ferroptosis-like death pathway in Trichosporon asahii.
- This pathway is dependent on iron accumulation and lipid peroxidation.
- This discovery presents a new ferroptosis-based strategy for developing antifungal therapies against resistant fungi.
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