Devising a Zfu2p targeted antifungal strategy that may preserve commensalism while suppressing Candida albicans virulence during vulvovaginal candidiasis.

Candida albicans is the leading cause of vulvovaginal candidiasis (VVC), a multifactorial disease of the lower female reproductive tract. Despite numerous studies, the molecular-pathophysiology during VVC and its commensal state within the host remains elusive. To address this, we performed a comprehensive computational analysis by integrating RNA-Seq datasets from both host and pathogen. Differentially expressed genes were identified and used to construct three network models: within the pathogen, host, and host-pathogen interaction. Subsequent inter-network nodes mapping enabled us to attain two distinct condition-specific fungal targeted networks in the host, during VVC (466 nodes and 496 edges) and commensal state (162 nodes and 176 edges), which were validated by condition-specific immune response by gene ontology analysis. Intending to target pathogenesis while preserving its commensal integrity, we identified an exclusive fungal protein Zfu2p that acts as a master regulator in the gene regulatory network of the pathogen. It promotes pathogenic attributes through its target gene RNR22 and interacts with the host protein UBC. Subsequently, the drug repurposing strategy coupled with molecular dynamics analysis identified Ergotamine as a promising candidate, which may disrupt biofilm formation while preserving commensal balance. This study offers insights into VVC pathophysiology and suggests a targeted therapy, though experimental validation of Ergotamine's efficacy remains essential.