Copper-only Superoxide dismutase 6 contributes to reactive oxygen species regulation, genotoxic stress tolerance, and virulence in Candida albicans.

Superoxide dismutase (SOD) is a major antioxidant enzyme that protects cells against reactive oxygen species (ROS)-mediated oxidative stress. The identification of a fungal-specific copper-only SOD family in Candida albicans (C. albicans) has revealed a previously unrecognized component of fungal oxidative stress defence, yet the role of SOD6 remains unclear. Here, we generated a sod6Δ/Δ mutant in C. albicans using a transient CRISPR/Cas9 approach and examined the contribution of SOD6 to virulence, ROS homeostasis, oxidative stress resistance, and genome maintenance. Compared with the wild-type (WT) strain, the sod6Δ/Δ mutant showed attenuated virulence in both the Galleria mellonella (G. mellonell) infection model and a murine systemic candidiasis model. This virulence defect occurred without detectable alterations in hyphal formation or other major pathogenicity-associated traits. Instead, the mutant accumulated higher intracellular and extracellular ROS levels and displayed increased sensitivity to hydrogen peroxide, zeocin, and camptothecin (CPT), consistent with impaired oxidative stress adaptation and genome maintenance. Transcriptomic analysis further revealed downregulation of genes involved in DNA replication and repair, with dpb4, which encodes a subunit of DNA polymerase epsilon required for DNA replication and genome stability, showing the greatest reduction. Together, these findings identify SOD6 as an important determinant of oxidative stress adaptation, genome maintenance, and pathogenic fitness in C. albicans.