• Identified a sub-cluster of Cryptococcus gattii VGI strains with distinct virulence profiles, highlighting the role of CAT2 in pathogenicity.
• Demonstrated that CAT2 knockout increases susceptibility to oxidative stress and antifungal drugs, and reduces virulence in a mouse model.
• Comparative transcriptomics revealed CAT2's involvement in oxidative stress response, metabolism, and sugar transport, providing mechanistic insights.
• Findings suggest potential for genotype-specific targeted therapies against cryptococcosis caused by C. gattii VGI.