首页|Isobavachalcone confers protection against Cryptococcusneoformans-induced ferroptosis in Caenorhabditis elegans via lifespan extension and GSH-GPX-1 axis modulation
Isobavachalcone confers protection against Cryptococcusneoformans-induced ferroptosis in Caenorhabditis elegans via lifespan extension and GSH-GPX-1 axis modulation
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The recent designation of Cryptococcus neoformans as a critical-priority fungal pathogen by the World HealthOrganization highlights the imperative need for novel antifungal agents with distinct mechanisms of action. Thisstudy elucidates the novel ferroptotic pathway underlying C. neoformans-induced cell death in Caenorhabditiselegans and investigates the therapeutic potential of isobavachalcone (IBC) through comprehensive evaluation ofcore biochemical markers: total glutathione (GSH), malondialdehyde, ferrous iron content, and lipid reactiveoxygen species (ROS). Integrated transcriptomic analysis via RNA-seq and subsequent RT-qPCR validationrevealed critical gene expression patterns associated with antiferroptotic regulation. Our findings demonstratethat C. neoformans infection initiates ferroptosis in C. elegans through iron-dependent lipid peroxidation cascades.Remarkably, IBC administration conferred significant protection against fungal-induced ferroptosis by restoringredox homeostasis-evidenced by elevated GSH levels, attenuated ROS accumulation, and decreased ferrous ironcontent. Mechanistic investigations identified IBC-mediated upregulation of SKN-1 and GSH biosynthesis genes,coupled with suppression of GPX-1 activity. These coordinated effects disrupted the iron-ROS amplification loop through modulation of the GSH-GPX-1 axis, ultimately extending host lifespan in C. neoformans-challenged models. Our results position IBC as a ferroptosis inhibitor with dual antioxidant and iron-chelating properties, offering a therapeutic strategy against cryptococcal infections through targeting of evolutionary conserved cell death pathways.
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