Sphingolipid Hydroxylation Governs Fungal Pathogenicity and Drug Susceptibility: Scs7 as a Druggable Target in Candida albicans

Sphingolipids are essential structural components of the fungal plasma membrane and key signaling hubs that orchestrate pathogenicity. While both fungi and mammals perform sphingolipid hydroxylation, they rely on evolutionarily divergent enzymatic systems, establishing a biochemical divergence exploitable for selective targeting. Here, through a screening of sphingolipid metabolic genes, we identify the sphingolipid -hydroxylase Scs7 as a central regulator of membrane homeostasis, virulence, and caspofungin susceptibility in Candida albicans. Genetic ablation of SCS7 depletes hydroxylated sphingolipids, disrupts memberane organization, and compromises cell wall integrity, which collectively impair hyphal morphogenesis, biofilm formation, and stress tolerance through blockade of the cAMP-PKA signaling axis. In a murine cutaneous infection model, SCS7 deletion markedly attenuates fungal burden, hyperinflammation, and epidermal barrier disruption, underscoring its non-redundant role in host-pathogen interaction. Leveraging the fungus-specific architecture of Scs7, we performed virtual screening and identified resveratrol as a natural Scs7 inhibitor. Resveratrol recapitulates the lipidomic and phenotypic defects of SCS7 deletion and synergizes with caspofungin to enhance fungal killing. Our study establishes sphingolipid -hydroxylation as a master determinant of fungal membrane fitness and validates Scs7 as a promising, fungus-specific antifungal target with dual anti-virulence and chemosensitizing activities.