Reactive Oxygen Species-Responsive Signaling Networks and Oxidative Stress Adaptation in Critical Priority Fungal Pathogens

Invasive fungal diseases (IFDs) are a global health threat, especially among immunocompromised populations, due to their high mortality rates and the increasing prevalence of antifungal resistance. In recognition of this threat, the World Health Organization (WHO) has designated Cryptococcus neoformans, Candida auris, Aspergillus fumigatus, and Candida albicans as critical-priority fungal pathogens. During host infection, host-derived reactive oxygen species (ROS) function as potent antimicrobial molecules, whereas fungal-derived ROS act as intracellular signaling mediators regulating oxidative stress adaptation, metabolism, virulence, and antifungal tolerance. Although oxidative stress responses have been extensively investigated in individual fungal pathogens, a comprehensive comparative analysis of oxidative stress signaling across these critical fungal pathogens remains limited. This review systematically compares oxidative stress sensing and signaling networks in the four WHO critical-priority fungal pathogens and classifies oxidative stress-associated pathways into conserved, and species-specific regulatory mechanisms. Conserved pathways, including HOG-MAPK, calcineurin, cAMP-PKA, cell wall integrity, and thioredoxin-dependent signaling, are discussed alongside pathogen-specific adaptations that promote biofilm formation, capsule and melanin production, polarized growth, morphogenesis, immune evasion, and antifungal resistance. By integrating conserved and divergent oxidative stress signaling mechanisms, this review provides a comparative framework that advances our understanding of fungal pathogenesis and highlights potential targets for the development of broad-spectrum and species-specific antifungal therapies.