ZCF4-dependent suppression of MMP-9 drives virulence in fluconazole-resistant Candida auris

While multidrug-resistant Candida auris poses a global threat to public health, the impact and mechanism of drug resistance on fungal virulence remain unclear. By employing the same-parent-derived fluconazole-resistant C. auris strains, this study utilized in vitro screening and host–pathogen co-culture models. Labile zinc was visualized using the fluorescent probe Zinpyr and Zinquin. Mechanisms identified via dual RNA sequencing were further validated using genetic mutants and pharmacological inhibitors. For in vivo validation, a fly survival model was employed, followed by an infection model in C57BL/6J mice (total n = 84). Mice were challenged with C. auris via lateral tail vein injection and oral gavage. Efficacy was evaluated through daily survival monitoring, fungal burden via colony-forming unit (CFU) counting, histopathological examination of tissue sections, and cytokine level measurement. We revealed that fluconazole-resistant C. auris exhibits enhanced fitness and resistance to macrophage killing under zinc deficiency by mobilizing intracellular zinc. Mechanistically, the inhibition of gene encoding Zn(Ⅱ)2Cys6 transcription factor 4 (ZCF4) contributes to C. auris resistance to macrophage killing by suppressing the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway and downstream matrix metalloproteinase-9 (MMP-9) activity under low-zinc conditions. Furthermore, dietary zinc deficiency promotes the virulence of fluconazole-resistant C. auris. These findings highlight a fitness advantage of fluconazole-resistant C. auris under zinc-deficient conditions through host–fungal interactions, offering a potential nutrient intervention strategy against fungal infection.