Isobavachalcone confers protection against Cryptococcus neoformans-induced ferroptosis in Caenorhabditis elegans via lifespan extension and GSH-GPX-1 axis modulation

Abstract

The recent designation of Cryptococcus neoformans as a critical-priority fungal pathogen by the World Health Organization highlights the imperative need for novel antifungal agents with distinct mechanisms of action. This study elucidates the novel ferroptotic pathway underlying C. neoformans-induced cell death in Caenorhabditis elegans and investigates the therapeutic potential of isobavachalcone (IBC) through comprehensive evaluation of core biochemical markers: total glutathione (GSH), malondialdehyde, ferrous iron content, and lipid reactive oxygen species (ROS). Integrated transcriptomic analysis via RNA-seq and subsequent RT-qPCR validation revealed critical gene expression patterns associated with antiferroptotic regulation. Our findings demonstrate that 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 restoring redox homeostasis-evidenced by elevated GSH levels, attenuated ROS accumulation, and decreased ferrous iron content. 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.