Vacuolar iron export alters the synergy between doxycycline and fluconazole by affecting cidal ROS levels in <i>Candida albicans</i>

, yet many cells survive above the minimal inhibitory concentrations (MIC) by growing slowly, which can prolong infection and foster resistance. We show that intracellular iron homeostasis alters the fluconazole characteristics by affecting ROS accumulation in mitochondria, and that this is the molecular mechanism underlying the combination therapy of fluconazole and doxycycline. These results place iron release from the vacuole at the center of azole responses, suggesting novel ways to boost azole efficacy.