Candida albicans, a World Health Organization critical-priority fungal pathogen, represents the predominant cause of candidemia. Therapeutic failure is sometimes driven by antifungal tolerance, a phenotype distinct from resistance, whose underlying mechanisms remain incompletely defined. Here, we identify the peroxisomal protein Pex8 as a key regulator of tolerance to both azoles and amphotericin B. Although neither deletion nor overexpression of PEX8 altered minimum inhibitory concentrations, both modifications significantly reduced drug tolerance, as demonstrated by reduced fractional growth (FoG20) and impaired survival under drug pressure. RNA-seq analysis showed that PEX8 overexpression leads to downregulation of ergosterol biosynthesis genes and remodeling of stress-response pathways, suggesting a possible transcriptional basis for the loss of azole tolerance. Complementary lipidomic profiling demonstrated that PEX8 genetic manipulations induce extensive membrane lipid remodeling, characterized by specific alterations in ceramide and lysophospholipid subclasses, thereby revealing an ergosterol-independent mechanism underlying amphotericin B tolerance attenuation. Phenotypically, PEX8 overexpression attenuated serum-induced hyphal morphogenesis and reduced virulence in a Galleria mellonella infection model, consistent with downregulation of hyphal-associated and virulence-related genes. Our findings establish Pex8 as a central coordinator of oxidative stress adaptation, membrane homeostasis, filamentation, and pathogenicity, revealing a promising target for combating antifungal tolerance.
Xi et al. (Tue,) studied this question.