Integrated Cellular Stress Networks in Human‐Pathogenic Fungi: Evolutionary Origins, Ecological Adaptation, and Consequences for Infection

Fungal stress responses are frequently discussed in relation to virulence and antifungal resistance, yet most underlying systems have deeper evolutionary histories and function across diverse ecological contexts. This review integrates evolutionary, ecological, and molecular perspectives on stress adaptation in major human-pathogenic fungi. Environmental pressures, including temperature fluctuations, water and nutrient limitation, hypoxia, microbial competition, predation, and antifungal exposure, can shape stress-response capacities before or independently of human infection. We examine major molecular systems involved in fungal stress adaptation, including chaperone networks, HOG and cell-wall-integrity signaling, pH and hypoxia responses, the unfolded protein response, autophagy, redox signaling, and mitochondrial retrograde signaling. These systems interact through shared regulators and physiological outputs to maintain cellular homeostasis. Although core components are often conserved, their regulatory connections and phenotypic outputs can differ substantially among fungal lineages. During host association, these evolutionarily shaped and subsequently modified networks can support adaptation to immune, metabolic, physicochemical, and therapeutic stresses. Their contributions to antifungal tolerance and persistence should be distinguished from stable resistance. We propose that fungal pathogenicity represents one ecological context in which pre-existing and subsequently modified stress-response capacities are deployed, rather than assuming that infection-associated functions necessarily reveal their evolutionary origins.