Peroxin Pex8 couples stress responses, antifungal tolerance and virulence regulation in Candida albicans

ABSTRACT:

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. Mechanistically, RNA-seq analysis revealed that PEX8 overexpression suppresses ergosterol biosynthesis genes and reprograms stress-response pathways, providing a molecular basis for the observed azole tolerance attenuation. 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.

INSTRUMENT(S): Liquid Chromatography MS -

PROVIDER: MTBLS13170 | MetaboLights | 2026-03-12

REPOSITORIES: MetaboLights