The unfolded protein response is a potential therapeutic target in pathogenic fungi

Pathogenic fungal infections cause significant morbidity and mortality, particularly in immunocompromised patients. The frequent emergence of multidrug-resistant strains challenges existing antifungal therapies, driving the need to investigate novel antifungal agents that target new molecular moieties. Pathogenic fungi are subjected to various environmental stressors, including pH, temperature, and pharmacological agents, both in natural habitats and the host body. These stressors elevate the risk of misfolded or unfolded protein production within the endoplasmic reticulum (ER) which, if not promptly mitigated, can lead to the accumulation of these proteins in the ER lumen. This accumulation triggers an ER stress response, potentially jeopardizing fungal survival. The unfolded protein response (UPR) is a critical cellular defense mechanism activated by ER stress to restore the homeostasis of protein folding. In recent years, the regulatory role of the UPR in pathogenic fungi has garnered significant attention, particularly for its involvement in fungal adaptation, regulation of virulence, and drug resistance. In this review, we comparatively analyze the UPRs of fungi and mammals and examine the potential utility of the UPR as a molecular antifungal target in pathogenic fungi. By clarifying the specificity and regulatory functions of the UPR in pathogenic fungi, we highlight new avenues for identifying potential therapeutic targets for antifungal treatments.