In recent years, the role of sphingolipids in pathogenic fungi, in terms of pathogenicity and resistance to azole drugs, has been a rapidly growing field. This review describes evidence about the roles of sphingolipids in azole resistance and fungal virulence. Sphingolipids can serve as signaling molecules that contribute to azole resistance through modulation of the expression of drug efflux pumps. They also contribute to azole resistance by participating in various microbial pathways such as the unfolded protein response (UPR), pH‐responsive Rim pathway, and pleiotropic drug resistance (PDR) pathway. In addition, sphingolipid signaling and eisosomes also coordinately regulate sphingolipid biosynthesis in response to azole‐induced membrane stress. Sphingolipids are important for fungal virulence, playing roles during growth in hosts under stressful conditions, maintenance of cell wall integrity, biofilm formation, and production of various virulence factors. Finally, we discuss the possibility of exploiting fungal sphingolipids for the development of new therapeutic strategies to treat infections caused by pathogenic fungi.

In recent years, the role of mitochondria in pathogenic fungi in terms of azole resistance and fungal pathogenicity has been a rapidly developing field. In this review, we describe the molecular mechanisms by which mitochondria are involved in regulating azole resistance and fungal pathogenicity. Mitochondrial function is involved in the regulation of drug efflux pumps at the transcriptional and posttranslational levels. On the one hand, defects in mitochondrial function can serve as the signal leading to activation of calcium signaling and the pleiotropic drug resistance pathway and, therefore, can globally upregulate the expression of drug efflux pump genes, leading to azole drug resistance. On the other hand, mitochondria also contribute to azole resistance through modulation of drug efflux pump localization and activity. Mitochondria further contribute to azole resistance through participating in iron homeostasis and lipid biosynthesis. Additionally, mitochondrial dynamics play an important role in azole resistance. Meanwhile, mitochondrial morphology is important for fungal virulence, playing roles in growth in stressful conditions in a host. Furthermore, there is a close link between mitochondrial respiration and fungal virulence, and mitochondrial respiration plays an important role in morphogenetic transition, hypoxia adaptation, and cell wall biosynthesis. Finally, we discuss the possibility for targeting mitochondrial factors for the development of antifungal therapies.

Ergosterol plays a dual role in fungal pathogenesis and azole resistance, driving key advancements in the understanding of its biosynthesis regulation. This review integrates the latest research progress on the regulation of fungal ergosterol biosynthesis and its role in drug resistance and pathogenicity. We comprehensively discuss the functions of key enzymes (such as Erg11p/Cyp51A, Erg6p, Erg3p, and Erg25p) in the mevalonate, late, and alternative pathways. Notably, we highlight the complex regulation of cyp51A expression by factors such as SrbA, AtrR, CBC, HapX, and NCT in Aspergillus fumigatus, and elucidate the distinctive roles of Upc2, Adr1, and Rpn4 in Candida species. Importantly, we summarize recent discoveries on the CprA-dependent regulation of Cyp51A/Erg11p and heme-mediated stability control. Based on these findings, we propose innovative antifungal strategies, including dual-target inhibition and multi-enzyme inhibition by natural products, which provide novel insights and potential directions for the development of next-generation antifungal therapies.

Knowledge of ROS detoxification in fungal pathogens is useful in the design of new antifungal drugs and could aid in the study of oxidative stress resistance mechanisms. In this study, we demonstrate that OxrA protein localizes to the mitochondria and functions to protect against oxidative damage.

Aspergillus fumigatus can cause severe invasive aspergillosis in immunocompromised individuals. Copper, an essential but potentially toxic trace element for A. fumigatus, plays a critical role at the host-pathogen axis during infection. Accumulating evidence demonstrates that the host utilizes copper compartmentalization within macrophages to combat A. fumigatus infection. To survive under host-imposed copper toxicity, A. fumigatus has evolved sophisticated machinery to regulate copper homeostasis. Thus, targeting molecular pathways critical for copper homeostasis regulation provides an opportunity to improve therapeutic options for aspergillosis caused by A. fumigatus. In this review, we describe the copper homeostatic mechanisms by which A. fumigatus acquires and controls copper levels and explore the responses of the pathogen to altered copper levels in the host. Finally, we discuss the regulatory mechanisms of copper homeostasis that could be targeted for antifungal drug development