Isobavachalcone effectively inhibits the growth of <i>Candida albicans</i>

<i>Candida albicans</i> (<i>C. albicans</i>) is a commensal, drug-resistant opportunistic pathogen, and the eradication of invasive candidiasis represents a significant clinical challenge. This study investigated the inhibitory effect of isobavachalcone (IBC) on <i>C. albicans</i> growth and elucidated its mechanism. The antifungal activity of IBC was evaluated using minimum inhibitory concentration 90% (MIC₉₀) and minimum fungicidal concentration (MFC), combined with murine vaginitis and oral thrush models to assess <i>in vivo</i> efficacy. An MTT assay was used to assess drug safety. Mechanistic investigations included cell membrane/wall damage assessments, virulence factor inhibition, oxidative stress evaluation, ATP metabolism analysis, protein expression profiling, and target identification (including RT-qPCR, inhibitor intervention experiments, and related methodologies). The antifungal potency of IBC against <i>C. albicans</i> was demonstrated with a MIC₉₀ of 2 µg/mL and an MFC of 8 μg/mL. Against strain S393, IBC exhibited potent efficacy with median effective and effective concentrations of 1.301 µg/mL and 1.449 µg/mL, respectively. <i>In vivo</i>, IBC significantly alleviated vulvovaginal candidiasis and oropharyngeal thrush, outperforming fluconazole in therapeutic efficacy and mucosal protection. Mechanistic studies revealed that IBC prevented fungal invasion by inhibiting <i>C. albicans</i> adhesion and colonization on mucosal surfaces, mitigated inflammation through suppression of proinflammatory cytokine release, and downregulated the expression of <i>ADE13</i>, <i>TPI1</i>, and <i>ADK1</i> genes, with <i>ADK1</i> demonstrating the most significant suppression. Furthermore, IBC specifically bound to ADK1, inhibiting ATP synthesis and disrupting cellular energy metabolism in <i>C. albicans</i>. IBC represents a promising antifungal drug that acts by downregulating the <i>ADE13</i>, <i>TPI1</i>, and <i>ADK1</i> genes. Its downregulation of ADK1 leads to impaired ATP synthesis, induced DNA damage, and suppressed fungal proliferation.