Adh1-Car1 axis regulates dimorphic transition in Candida albicans by suppressing hyphal hyperelongation.

Candida albicans, a prevalent opportunistic fungal pathogen, employs dimorphic transition (yeast-to-hypha) as a central strategy for host tissue invasion and immune evasion. Although prior studies have linked ADH1 deletion to attenuated virulence phenotypes such as impaired hyphal formation, the molecular mechanism underlying this phenomenon remains elusive. Here, we report that ADH1 knockout strains exhibit a striking hyperelongation of hyphae, deviating from the characteristic branched architecture observed in wild-type strains. Transcriptomic profiling identified arginine metabolism as the most significantly activated pathway in adh1Δ/Δ mutants, with marked upregulation of CAR1, encoding a key arginase. Crucially, pharmacological or genetic inhibition of Car1 activity fully restores wild-type hyphal morphology in ADH1 knockout strains, unequivocally establishing that ADH1 governs hyphal development through repression of CAR1 expression. Our findings delineate the Adh1-Car1 metabolic axis as a master regulator of dimorphic switching in C. albicans: while Adh1 constrains Car1 to maintain balanced hyphal branching, its deletion triggers arginine metabolic flux dyshomeostasis, driving uncontrolled hyphal hyperelongation. This work redefines the functional paradigm of Adh1 beyond its canonical role in ethanol metabolism, positions fungal metabolic rewiring as a direct driver of morphogenic plasticity, and nominates the Adh1-Car1 axis as a high-value target for antifungal interventions.