Molecular frontiers of fungal autophagy: from molecular mechanisms to potential targets for antifungal drug discovery.

Given the rising incidence of infections caused by clinically important pathogenic fungi such as Candida, Aspergillus and Cryptococcus, there is a growing urgency to systematically explore novel strategies for antifungal therapy. Fungal autophagy, a conserved mechanism for cellular degradation and stress response, serves a central role in maintaining cellular homeostasis, promoting biofilm formation, and enhancing drug tolerance. Its regulatory network has thus emerged as a key target for elucidating the mechanisms underlying drug resistance. This review first details the induction mechanisms of autophagy, including the processes through which nutritional starvation and energy stress regulate autophagy initiation via signaling pathways such as TORC1 and Snf1/AMPK. A systematic outline of the main stages of autophagosome formation is also provided, which is essential for understanding the conservation and diversity of autophagy among eukaryotes (particularly in yeast and pathogenic fungi). In terms of regulatory mechanisms, autophagy responds to oxidative, endoplasmic reticulum, and osmotic stresses through pathways involving Yap1, Hog1 MAPK, and the unfolded protein response (UPR), and participates in multiple selective autophagy processes, thereby helping to maintain cellular homeostasis. These insights are valuable for elucidating the adaptive strategies employed by fungi in complex environments. Additionally, particular emphasis is placed on the relationship between fungal autophagy and antifungal drug resistance in Candida, Aspergillus and Cryptococcus, as well as major classes of antifungal agents that target fungal autophagy. This analysis offers a fresh molecular perspective for understanding the pathogenicity and drug resistance of clinically relevant fungal pathogens, and supports the development of novel antifungal drugs with unique mechanisms of action. The information presented herein is expected to provide a theoretical foundation and technical guidance for revealing conserved biological processes, advancing antifungal drug development, and improving the performance of fungal cell factories.