Mechanisms and regulation of iron uptake and the role of iron in pathogenesis of Candida albicans

Abstract

Candida albicans is a primary pathogen implicated in invasive fungal infections. Through its intricate iron uptake and regulatory systems, C. albicans adeptly adapts to various iron-rich environments, circumventing the growth and virulence restrictions imposed by the host's nutritional immunity and intensifying infection severity. This fungus activates the Sef1-Sfu1-Hap43 iron homeostasis regulatory circuit via iron bioavailability sensors (iron-sulfur cluster assembly system). This activation precisely regulates multiple iron uptake pathways, including the high-affinity iron reduction system, heme-iron uptake pathway, and siderophore uptake system, as well as genes involved in iron utilization and storage, thus ensuring effective iron acquisition and maintaining iron homeostasis across diverse environmental conditions and developmental stages. Conversely, disruptions in iron metabolism markedly diminish C. albicans's pathogenic potential by impairing mitochondrial function, suppressing hyphal formation, limiting fungal colonization, and reversing antifungal drug resistance. This review presents a comprehensive analysis of the mechanisms governing iron uptake and regulation in C. albicans and examines the consequences of impaired iron homeostasis on mitochondrial function, hyphal formation, infection progression, and drug resistance. Our goal is to provide a theoretical framework to better understand the pathogenesis of C. albicans and to support the development of targeted therapeutic strategies against this resilient pathogen.

Keywords: Candida albicans; iron absorption; iron homeostasis; regulatory networks; virulence.