Aloe emodin disrupts Candida albicans mitochondrial iron homeostasis against its hyphal development and oral candidiasis.

Candida albicans, a critical pathogen listed on the WHO fungal priority pathogens list, is a major cause of candidiasis and candidemia, particularly in immunocompromised populations. The lack of novel antifungal drugs and the increasing prevalence of drug resistance underscore the urgent need for new therapeutic strategies. By screening compounds derived from Aloe vera using hyphal induction assays, we identified aloe emodin (AE) as a potent inhibitor of C. albicans hyphal development. We demonstrate for the first time that AE, at concentrations of 50-100 μg/mL that do not affect fungal growth, significantly inhibits C. albicans hyphal development and its infections to oral epithelial cells without cytotoxicity. The confocal observation and following transcriptome and metabolome analysis demonstrate that AE localizes to fungal mitochondria and chelates iron, thereby disrupting iron homeostasis. These effects lead to mitochondrial dysfunction and metabolic reprogramming, particularly by impairing succinate dehydrogenase 2 activity, thereby reducing ATP and cAMP production. The decrease in cAMP levels leads to downregulation of the cAMP-PKA signaling pathway, a central regulator of hyphal development, ultimately suppressing hyphal growth. Mitochondrial function and metabolic assays, together with validation using mutants of the cAMP-PKA pathway, further confirmed the mechanism underlying the anti-hyphal activity of AE. AE at 50-100 μg/mL administered via drinking water also significantly reduced fungal burden and tissue damage in an oropharyngeal candidiasis model, which is similar with clinical antifungal nystatin. Collectively, our findings indicate that AE is a promising candidate for development as a therapeutic agent for oral candidiasis. KEY POINTS: • Aloe emodin disrupts mitochondrial iron homeostasis to remodel metabolism in C. albicans. • Aloe emodin downregulates the cAMP-PKA pathway to inhibit C. albicans hyphae. • Aloe emodin functions as a novel candidate for treating infections caused by C. albicans.