Iron acquisition mechanisms of human skin-associated fungi

Abstract

Human skin presents a nutritionally restrictive environment in which iron availability is tightly controlled by epidermal iron recycling, host iron-binding proteins, and nutritional immunity. Thus, skin-associated fungi must acquire iron from limited, often host-sequestered sources. This minireview summarizes current knowledge on iron acquisition systems in the fungal taxa most consistently identified in the human skin mycobiome: Malassezia species, Candida albicans, Candida auris, Rhodotorula mucilaginosa, and dermatophytes. These fungi appear to rely on diverse strategies, including reductive iron uptake, heme and ferritin utilization, and siderophore-mediated iron scavenging. However, our mechanistic understanding differs greatly among species. In C. albicans, several uptake systems have been characterized, but their direct roles in cutaneous colonization versus invasive disease remain unclear. In C. auris, persistent skin colonization is a critical biological feature, but iron sources and uptake pathways supporting its survival, as well as how they intersect with its notorious antifungal resistance, remain largely unresolved. Rhodotorula mucilaginosa and dermatophytes employ siderophore-associated iron acquisition, and yet the relevant transporters and regulatory mechanisms remain poorly characterized. Most notably, despite Malassezia’s dominance in the human skin mycobiome and its uncertain status as commensal, pathogen, or both, its iron acquisition strategies remain almost completely unexplored at the functional level. Understanding how skin-associated fungi compete for and acquire iron in the cutaneous environment will provide important insights into fungal commensalism, niche adaptation, and the pathogenic transition.

This review summarizes current knowledge on iron acquisition systems in major skin-associated fungi, including Malassezia species, Candida albicans, Candida auris, Rhodotorula mucilaginosa, and dermatophytes.

Introduction

As a critical co-factor in fundamental biological processes such as oxygen transport, cellular respiration, DNA synthesis, and host defense, iron is an indispensable trace element for almost all living organisms (Haschka et al. 2021). However, its essentiality is inextricably linked to its potential cytotoxicity. When present in excess, particularly in its reduced ferrous form (Fe²⁺), iron catalyzes the generation of highly reactive hydroxyl radicals via Fenton reactions, causing detrimental oxidative stress, which leads to the accumulation of reactive oxygen species and, eventually, extensive macromolecule damage and lipid peroxidation (Jomova and Valko 2011). Thus, cells must strictly regulate iron acquisition, utilization, and storage.

The human epidermis displays a reverse gradient of iron, with levels decreasing from the basal layer to the stratum corneum, and a small portion of epidermal intracellular iron is lost through continuous desquamation (Asano et al. 2017). Epidermal keratinocytes establish a pronounced vertical iron gradient, meticulously regulating iron import, storage, recycling, and release to prevent local toxicity as well as iron deficiency while meeting their high cellular demands. In the highly proliferative, undifferentiated basal layer of the epidermis, iron is actively imported from the bloodstream. This uptake is primarily mediated by transferrin receptor 1 (TfR1), which internalizes circulating holotransferrin, and divalent metal transporter 1 (DMT1), which facilitates iron’s release from endosomal compartments into the cytoplasm. Once inside, excess labile iron is sequestered by ferritin, a highly conserved multimeric protein complex capable of storing thousands of iron atoms as a largely redox-inactive ferric mineral core, thereby limiting iron-catalyzed reactive oxygen species generation and lipid peroxidation (Chrayteh et al. 2026).

Humans lose ~1 mg of iron daily through desquamation at the skin surface, and the epidermis has evolved an iron recycling system to minimize this loss to the environment (Surbek et al. 2023). Indeed, as desquamation increases, systemic iron levels are significantly reduced. For example, it was suggested that up to 2.5 mg/day of iron can be lost in patients with enhanced desquamation in a patient with psoriasis (Surbek et al. 2023). In the epidermis, iron recycling mainly occurs in the upper layers. As keratinocytes differentiate and migrate outward, forming the suprabasal and granular layers, their iron metabolism undergoes a dramatic shift from focusing on import to active recycling. In the upper granular layer, enzymes such as heme oxygenase-1, which degrades cellular heme to release ferrous iron, carbon monoxide, and biliverdin, are constitutively expressed. This liberated iron is then exported into the extracellular space via the transmembrane exporter ferroportin (FPN) (Surbek et al. 2023). Oxidation of this exported iron is likely mediated by localized ferroxidases, such as hephaestin-like 1, which is prominently expressed in the outer epidermis and within specialized skin appendages. Ultimately, this highly efficient epidermal iron recycling system ensures only a minimal fraction of iron is lost to the environment when the terminally differentiated corneocytes of the stratum corneum are shed (Asano et al. 2017, Surbek et al. 2023). Beyond this keratinocyte-derived recycling pool, small amounts of iron also reach the skin surface via eccrine sweat and sebaceous secretions; however, the amounts made available through these routes are generally considered quantitatively minor relative to the iron recycled through desquamation, and their contribution to iron availability for cutaneous microbes remains poorly defined (Surbek et al. 2023).

By actively recycling iron in the granular layer, the host not only minimizes loss but also creates an iron-depleted environment to inhibit microbial colonization, one of a number of defense strategies defined as nutritional immunity (Murdoch and Skaar 2022). The skin and its resident immune cells also deploy several dynamic defense mechanisms to enforce this nutritional immunity. Upon detecting microbial invasion, epidermal keratinocytes and localized neutrophils dramatically upregulate the production and secretion of metal-chelating proteins, such as calprotectin, further minimizing metal availability to microbes on the surface (Martinsson et al. 2005). In addition to calprotectin, the host releases lactoferrin, an iron-binding glycoprotein that strictly sequesters local iron, to achieve antimicrobial effects (Actor et al. 2009, Rizzi et al. 2025). Neutrophils, after migrating to the site of infection, secrete lipocalin-2, a protein that binds microbial siderophores, blocking iron acquisition, from their secondary granules (Schroll et al. 2012, Cassat and Skaar 2013). Simultaneously, the skin utilizes systemic iron-regulatory hormones for local immune defense. Hepcidin, primarily recognized as a liver hormone, is produced under iron overload conditions, following microbial infection, and during inflammation to restrict systemic iron levels by binding to FPN and inducing its degradation. During infections, epidermal keratinocytes robustly synthesize hepcidin, which functions via a chemokine-dependent pathway to promote the production of CXCL1, rapidly recruiting pathogen-killing neutrophils to the invasion site (Asano et al. 2017, Malerba et al. 2020).

Given that the skin is the human body’s largest organ, impeding iron acquisition at the skin’s surface establishes a formidable physical and immunological barrier against the environment’s and microbes’ continuous challenges (Surbek et al. 2023, Chrayteh et al. 2026), and several studies have investigated the intricate genetic and molecular mechanisms that govern how pathogenic and commensal microbes survive and thrive within this unique ecological niche (Heilbronner and Foster 2021, Oliveira et al. 2021, Mlynarczyk-Bonikowska and Rudnicka 2025). While the battle for iron between the host and bacterial pathogens has been extensively studied, the iron acquisition strategies of skin-associated fungi are relatively unexplored. Fungi are integral members of the skin microbiome, and their survival is strictly dependent on their ability to acquire trace nutrients, including iron. Therefore, to fully understand fungal colonization, commensalism, and pathogenesis in human skin, understanding how they survive and thrive in this highly restrictive niche is mandatory.

A diverse array of fungal species inhabit human skin, with Malassezia being the dominant genus, along with Candida, Aspergillus, and Rhodotorula, and various other fungi, including dermatophytes, as significant components (Findley et al. 2013, Byrd et al. 2018, Nguyen and Kalan 2022). To successfully colonize the skin and establish infections, fungi must subvert formidable nutritional immunity, and iron deprivation in particular. Iron acquisition mechanisms in a few opportunistic fungi, such as Candida species, have been extensively studied. However, most of these studies investigated systemic or mucosal infection models, and skin-specific iron uptake and regulation mechanisms are relatively less well-characterized. Furthermore, iron acquisition in the majority of dominant fungi found in the skin environment, e.g. Malassezia, is largely unexplored. In this review, we summarize the current understanding of iron uptake systems in skin-associated fungi and their function in the skin environment. Throughout, we have aimed to clearly distinguish mechanisms that have been experimentally demonstrated in a given fungal genus or species, from those that are biologically plausible but remain untested; where direct evidence in the skin environment is lacking, we clearly identify this as a knowledge gap rather than inferring a mechanism from non-cutaneous infection models.

Malassezia species

Species of the genus Malassezia are basidiomycetous yeasts. To date, 19 Malassezia species have been reported, including the most recently identified species, M. polysorbatinonusus, isolated from a seborrheic dermatitis lesion (Hiruma et al. 2025). Among them, M. restricta and M. globosa dominate the mycobiomes of most areas of human skin, with limited proportions represented by other Malassezia species, such as M. sympodialis, M. arunalokei, and M. slooffiae (Hobi et al. 2022). Additionally, two novel metagenome-assembled genomes representing potentially undescribed Malasseziaceae species were isolated from the skin of individuals residing in indigenous communities of the Amazon (Durack et al. 2025).

Although Malassezia species are permanent residents of healthy human skin, several, most notably M. restricta, M. globosa, and M. furfur, are also strongly associated with common dermatologic conditions, including seborrheic dermatitis, dandruff, pityriasis versicolor, and flares of atopic dermatitis, and these species can be recovered from both healthy and diseased skin (Vijaya Chandra et al. 2020). The factors governing their transition between a commensal and a disease-associated state remain incompletely understood, and it is currently unclear whether altered iron acquisition or iron-responsive gene expression contributes, as it does for several other fungal pathogens (Noble 2013).

Malassezia have co-evolved with warm-blooded vertebrates over millions of years, resulting in extreme metabolic specialization. Their genomes are remarkably small (~7–9 Mb) and lack the genes for de novo fatty acid synthesis, making them dependent on host-derived lipids found in sebum (Wu et al. 2015, Park et al. 2017). For these reasons, Malassezia species possess an unusually high number of genes encoding lipases that degrade sebum into free fatty acids, a function crucial for their survival as lipophilic fungi (Park et al. 2021), some of which may trigger hyperproliferation and inflammation in the skin (DeAngelis et al. 2005, Pagac et al. 2025). While the direct influence of Malassezia lipases on iron bioavailability in the presence of sebum has not been explicitly investigated, they alter the local microenvironment, particularly its pH, and could potentially impact the solubility and availability of iron.

Currently, no study has suggested how Malassezia species acquire iron in the human skin environment. They may possess a classical siderophore-based iron utilization system or rely on xenosiderophores produced by other skin-associated microbes. Alternatively, reductive iron assimilation, functioning through cell surface reductases, ferrioxidases, and iron permeases, may participate in Malassezia’s iron acquisition system in the skin. Although its details still need to be explored, a previous study suggests that Malassezia species also possess a tightly regulated iron homeostasis system. The Malassezia lineage appears to have incorporated several bacterial genes through horizontal gene transfer, notably including those encoding flavohemoglobins, which are essential for nitric oxide detoxification and resistance to nitrosative stress indirectly supporting iron homeostasis by mitigating stress conditions that can disrupt iron metabolism (Ianiri et al. 2020). The integration of such genes into the Malassezia genome indicates strong evolutionary pressure to adapt to the competitive and hostile skin environment. In addition, a study reported that Malassezia members possess functional iron–sulfur (Fe–S) cluster pathways, as evidenced by the sensitivity of these species to antifungal agents targeting these pathways, such as zinc pyrithione (Park et al. 2018).

Genome sequences of multiple Malassezia species offer a way to generate testable hypotheses about iron acquisition, even in the absence of functional data. A comparative genomic analysis across 14 Malassezia species found extensive gene loss consistent with the genus’s reduced, lipid-dependent lifestyle, including loss of fatty acid synthase and several carbohydrate-active enzyme gene families, but this analysis did not specifically catalogue iron-related gene content (Wu et al. 2015). Similarly, the original M. globosa and M. restricta genome assemblies have not, to our knowledge, been systematically surveyed for homologs of the reductive iron uptake components FTR1/FET3, and CFEM-domain heme receptors of C. albicans (Roy and Kornitzer 2019), or of NRPS-type siderophore biosynthetic gene clusters. A dedicated survey of these gene families across the available Malassezia genomes, even without accompanying functional validation, would meaningfully clarify whether the genus retains the genomic capacity for reductive or siderophore-mediated iron acquisition or whether, as with its lipid metabolism, its iron-acquisition gene repertoire has undergone reductive evolution.

The obligate dependence of Malassezia on host-derived lipids may also have indirect consequences for its iron metabolism. In eukaryotic cells, mitochondrial fatty acid synthesis and Fe–S cluster biogenesis are generally mechanistically coupled. The mitochondrial acyl carrier protein, the central scaffold of the mitochondrial fatty acid synthesis pathway, also participates in the assembly of the Fe–S clusters used by the core cysteine desulfurase (Nfs1) cluster assembly machinery, and disrupting mitochondrial fatty acid synthesis impairs Fe–S cluster formation in S. cerevisiae (Pandey et al. 2024). Whether the loss of cytosolic fatty acid synthase in Malassezia species has similarly reshaped their dependence on, or regulation of, mitochondrial Fe–S cluster biogenesis has not been examined in this genus, but this connection offers a plausible, testable link between lipid dependency and iron metabolism in Malassezia that merits future investigation.

We currently do not know which iron source in the human skin environment Malassezia utilizes. Possible sources include the iron bound to the iron-binding proteins transferrin and lactoferrin, which typically restrict microbial access to iron. However, it has been shown that transferrin inhibits Malassezia growth (Bond et al. 2005), and the direct uptake of transferrin-sequestered iron has not been demonstrated. Additionally, Malassezia species appear to lack dedicated receptors for transferrin or lactoferrin (Bond et al. 2005, Brouwer et al. 2024). Further in-depth studies are required to elucidate iron acquisition and homeostasis in Malassezia and to reveal which iron source the fungus utilizes within the skin environment.

Candida albicans

Candida albicans, a polymorphic fungal species commonly found in the human body, is known to be both a commensal and an opportunistic pathogen. In healthy individuals, C. albicans most often appears as a commensal of mucosal surfaces, particularly those of the gastrointestinal and genitourinary tracts, but under compromising conditions, such as immune dysfunction, barrier disruption, antibiotic exposure, diabetes, maceration, or other local host alterations, it can become a pathogen and cause candidiasis (Kim and Sudbery 2011, Kumamoto et al. 2020). Clinically, C. albicans can cause a broad range of diseases, spanning superficial mucosal infections to life-threatening invasive candidiasis; superficial manifestations include oropharyngeal candidiasis, esophagitis, vulvovaginal candidiasis, and a variety of mucocutaneous infections, whereas invasive disease includes candidemia and disseminated candidiasis, primarily in hospitalized or otherwise highly vulnerable patients (Pappas et al. 2018, Lopes and Lionakis 2022). In the skin, C. albicans is mainly associated with cutaneous candidiasis, a group of infections that typically develop in warm, moist, occluded, or damaged sites, including intertrigo in skin folds, diaper dermatitis, erosio interdigitalis blastomycetica, candidal paronychia and onychia, and nail infections.

Cutaneous disease is favored under conditions that impair local barrier function or alter the skin microenvironment, including prolonged moisture, friction, obesity, diabetes, immunosuppression, and chronic inflammation; in such settings, C. albicans can exploit epithelial weaknesses, adhere to damaged surfaces, form hyphae, and trigger inflammatory responses that contribute to symptomatic disease (Kashem and Kaplan 2016, Taudorf et al. 2019, Lu et al. 2023, Lim et al. 2025). Although the skin is not usually considered the primary reservoir of commensal C. albicans, as the gut or mucosal surfaces are, it can clearly colonize and infect cutaneous sites under favorable conditions (Talapko et al. 2021, Lopes and Lionakis 2022, Song et al. 2024). This makes the skin an important niche for C. albicans in which it must adapt to a highly distinctive environment characterized by low water availability, variable pH levels, lipid-rich but nutrient-limited surfaces, multiple antimicrobial defenses, microbial competition, and restricted access to essential metals. Among these constraints, iron limitation is likely to be especially important, as iron is indispensable to the growth and virulence of C. albicans yet tightly controlled by the host (Noble 2013). Therefore, understanding how C. albicans acquires iron in the skin environment is critical to understanding both its cutaneous persistence as a commensal and its transition to pathogenic growth.

Since C. albicans shifts between a commensal and a pathogenic lifestyle depending on host and environmental cues (Kumamoto et al. 2020), it is likely that the iron acquisition systems described below are deployed differently depending on whether the fungus is behaving as a skin commensal or invading damaged tissue, though this distinction has not yet been directly tested in a cutaneous model.

The best characterized iron acquisition pathway in C. albicans is reductive iron uptake, in which extracellular ferric iron is first reduced to ferrous iron by cell-surface ferric reductases, principally Fre10 together with Fre7 (Knight et al. 2005, Jeeves et al. 2011), after which iron is re-oxidized by the multicopper ferroxidase Fet34 and transported across the plasma membrane by the high-affinity permease Ftr1 (Ramanan and Wang 2000, Ziegler et al. 2011), a pathway functionally homologous to the Fet3–Ftr1 system of Saccharomyces cerevisiae. Additional ferric reductases, including Frp1 and Fre2, are differentially regulated in response to iron chelation and alkaline pH, with Frp1 being particularly responsive (Baek et al. 2008), and Frp1, together with Frp2, has also been shown to mediate reduction of extracellular hemin (Fe³⁺-heme), a route preferred when C. albicans uses heme as an iron source (Fu et al. 2026). This diversity indicates that the reductive pathway is not a single static transporter system but a flexible, tunable set of surface iron-utilization machinery matched to the chemical form of the available iron and local pH. Among the pathway’s downstream components, Ftr1 is especially critical. Using a virulence phenotype established in a systemic murine infection model, rather than in cutaneous colonization, the loss of Ftr1 function was shown to severely disrupt growth under iron limitation and abolish the ability of C. albicans to establish systemic infection in mice, definitively identifying high-affinity iron uptake as a virulence determinant and making Ftr1 one of the most attractive iron-related antifungal targets in C. albicans (Ramanan and Wang 2000, Ziegler et al. 2011).

In addition to Frp1 and Frp2, C. albicans requires Rbt5, an extracellular GPI-anchored heme receptor containing the fungal-specific CFEM domain, to efficiently use hemin and hemoglobin as iron sources (Weissman and Kornitzer 2004), and more recent work has demonstrated that this process involves a relay network of extracellular heme-binding proteins, including Pga7 and Csa2, which cooperate to capture heme from host proteins and move it across the fungal cell wall toward the membrane (Roy and Kornitzer 2019). Deletion of PGA7 causes a pronounced defect in heme-iron utilization and reduces the virulence of C. albicans, showing that heme scavenging is a critical aspect between the C. albicans and host interaction (Kuznets et al. 2014). Once internalized, heme is degraded by the heme oxygenase Hmx1, the expression of which is induced by hemoglobin and which contributes to heme utilization and homeostasis (Pendrak et al. 2004); a recent study also indicated that C. albicans can use exogenous heme not only as an internalized iron source but also as a cell-surface iron source, reinforcing the versatility of this pathway (Weissman et al. 2021).

Heme, considered the most abundant form of iron in the human body, is a critical nutrient for many bacterial pathogens, such as S. aureus (Donegan 2022). The skin itself has mechanisms to recycle iron from heme during the turnover of keratinocytes, a process during which iron may be made accessible to microbes (Surbek et al. 2023). However, while C. albicans is capable of using heme and hemoglobin as iron sources in vitro and in systemic infection models, no study has directly demonstrated that such heme-derived iron utilization occurs in the skin environment specifically, and targeted skin-relevant studies are needed to address this.

Notably, C. albicans does not synthesize its own siderophores, but it can use xenosiderophores produced by other microorganisms. The gene SIT1/ARN1 encodes a siderophore transporter that mediates the uptake of ferrichrome-type siderophores and has been shown to contribute to epithelial invasion (Heymann et al. 2002). This function may be particularly relevant in polymicrobial environments, such as skin, where other bacteria and fungi release siderophores (Algadi et al. 2024, Choi et al. 2024). Thus, even when host-derived soluble iron is scarce, surrounding microbiota may indirectly expand the landscape of iron accessible to C. albicans, although direct experimental evidence that skin microbiota releases siderophores usable by C. albicans remains limited.

A particularly elegant adaptation of C. albicans is found in its ability to obtain iron from ferritin. The hypha-associated adhesin and invasin Als3 binds ferritin, enabling acquisition of iron directly from stored iron within the host (Almeida et al. 2008). This mechanism is morphology dependent and links invasive growth to iron scavenging, suggesting that hyphal development does not merely promote tissue penetration; it also unlocks otherwise inaccessible iron pools in the host. In the skin, this is highly relevant because ferritin is abundant in epidermal keratinocytes, and skin acts as an important iron repository. Therefore, ferritin-based iron acquisition may be particularly important for C. albicans once the superficial barrier is breached and the fungus encounters viable keratinocytes or damaged tissue.

Candida auris

Since its first description, C. auris, which was recently reclassified to Candidozyma auris (Liu et al. 2024), has become a major global healthcare-associated fungal pathogen due to its emerging multidrug-resistant (Kim et al. 2009, Satoh et al. 2009, Lee et al. 2011). Unlike many other Candida species, C. auris is notable for its ability to not only cause invasive infections but also survive on surfaces in healthcare settings and persistently colonize skin, especially that of hospitalized patients (Spivak and Hanson 2018). Moreover, C. auris is frequently resistant to fluconazole and often shows reduced susceptibility to amphotericin B, with echinocandin-resistant isolates also occasionally reported, making treatment challenging. Because of its rapid international emergence, antifungal resistance, and capacity for nosocomial spread, C. auris has been recognized as a critical-priority fungal pathogen by the World Health Organization (Casalini et al. 2024).

A clinically distinctive feature of C. auris is its marked skin tropism. Unlike other Candida species, C. auris efficiently colonizes skin, persists there for prolonged periods, and is readily shed into the surrounding environment. Infected patients can carry high fungal burdens on their skin, particularly at sites such as the axilla, groin, and nares, and this cutaneous reservoir is strongly linked to the contamination of bedrails, linens, medical devices, and other common healthcare facility surfaces. Thus, its persistence on skin is central to C. auris’ ability to spread efficiently in hospitals and long-term care facilities (Eix and Nett 2025).

This strong adaptation to the skin environment suggests that C. auris possesses physiological mechanisms that enable survival and persistence under the unique nutritional and physicochemical conditions of the cutaneous niche. Among these conditions, iron depletion is likely to be particularly important (Simm et al. 2022). Accordingly, C. auris’ success in the skin environment is expected to depend on efficient systems for iron acquisition and maintaining iron homeostasis, as well as other adaptations to iron-deficient conditions, and understanding these systems may provide important insight into its skin tropism, persistence, and pathogenic potential (Huang et al. 2021, Simm et al. 2022). Although direct studies of C. auris are limited, current findings suggest that during skin colonization, C. auris likely acquires iron by targeting host proteins that sequester iron, such as hemoglobin, transferrin, and ferritin. C. auris may employ mechanisms similar to those found in C. albicans, including heme acquisition pathways, reductive iron uptake systems, and siderophore-mediated uptake (Munoz et al. 2018, Simm et al. 2022, Gifford et al. 2025).

As heme is a highly bioavailable iron pool in animal tissues, fungal pathogens have evolved dedicated heme-acquisition systems. However, on a normal, intact epidermis, hemoglobin should be scarce, but in microabrasions, excoriated areas, catheter-exit skin, inflamed lesions, or other barrier disruption sites, erythrocyte-derived hemoglobin and free heme become much more accessible. Since C. auris preferentially colonizes skin and can penetrate damaged skin, heme is a very plausible iron source. Indeed, a study reported that C. auris possesses hemolytic activity, the characteristics of which imply the fungus may be able to liberate heme from erythrocytes (Kumar et al. 2015). However, direct experimental proof that C. auris can uptake and use heme or hemoglobin as an iron source is still missing. In addition, it should be noted that a comparative analysis of fungal heme acquisition mechanisms reported that the homolog of C. albicans’ FRP2 gene, which is responsible for the reduction of extracellular hemin, is absent in the genome of C. auris (Roy et al. 2022). This suggests that the heme uptake system in C. auris may be different, incomplete, or less well conserved relative to that in C. albicans.

The human epidermis contains abundant ferritin, especially in keratinocytes, and differentiated keratinocytes actively recycle iron before cornification. Thus, small amounts of recycled or released iron may appear locally during desquamation or inflammation or in damaged tissue. For a skin-adapted colonizer such as C. auris, scavenging iron from these limited local pools through high-affinity uptake is likely important. In C. albicans, ferritin is an exploitable iron source, with acquisition mediated through the hypha-associated adhesin and invasin Als3 (Almeida et al. 2008). However, an equivalent ferritin-acquisition mechanism has not been clearly demonstrated in skin-associated C. auris, though C. auris has a distinct adhesin repertoire, including ALS-family and other GPI proteins (Wang et al. 2024), so ferritin use remains biologically plausible, especially in damaged epidermis tissue where intracellular ferritin becomes exposed.

Transferrin iron uptake through a high-affinity reductive pathway has been clearly demonstrated in C. albicans, but intact skin is a much less transferrin-rich environment than serum or tissue fluids. Therefore, for C. auris, which is primarily found on superficial intact skin, transferrin is probably not the dominant source. However, on moist, damaged, or exudative skin, as well as in more invasive settings, where plasma proteins leak into tissue, transferrin may become a more relevant iron source. Therefore, it may be a conditional resource for C. auris. Furthermore, a transcriptome analysis suggested that C. auris possesses homologs of C. albicans’ FTR1 and FET3 genes, components of the high-affinity reductive iron uptake system responsible for transferrin uptake (Simm et al. 2022). Additionally, another iron-binding protein, lactoferrin, acts as a key component of the host’s nutritional immunity by sequestering iron and exerting direct antifungal effects, and while studies have demonstrated that lactoferrin inhibits the growth of Candida species, including C. auris (Brouwer et al. 2025, de-la-Fuente et al. 2025), no studies have yet explored whether C. auris can utilize lactoferrin-bound iron.

During infection, C. auris exhibits an upregulation of xenosiderophore transmembrane transporter candidate (XTC) genes, which are strongly enriched across all Candida clades (Gifford et al. 2025). These transporters may play a role in iron acquisition, supporting the survival and virulence of C. auris in the host environment. While direct evidence of siderophore production in C. auris is limited, the presence of siderophore transporter genes and the upregulation of siderophore-related pathways in transcriptomic studies suggest that C. auris can utilize both endogenous and exogenous siderophores to acquire iron in the iron-deficient skin environment.

Beyond its nutritional roles, in C. auris, iron and mitochondrial metabolism may also intersect with antifungal resistance. The disruption of iron homeostasis and mitochondrial function has been shown to resensitize resistant C. auris strains to existing antifungals (Simm et al. 2022), and iron-dependent mitochondrial pathways have been linked to azole resistance across Candida species more broadly (Van Genechten et al. 2024). This connection underscores the broader clinical relevance of understanding C. auris’s iron physiology, which has applications beyond its role in nutrient acquisition alone.

Additional Candida species aside from C. albicans and C. auris, e.g. C. parapsilosis, C. glabrata (Nakaseomyces glabratus), and C. tropicalis, are occasionally isolated from human skin but are not consistently detected and are markedly less prevalent in the healthy cutaneous mycobiome than the taxa considered here (Findley et al. 2013, Byrd et al. 2018). Additionally, skin-specific iron-acquisition data for these species are essentially absent. Therefore, in this minireview, we have restricted our discussion to the Candida species most consistently identified as residents of human skin.

Rhodotorula mucilaginosa

The genus Rhodotorula, basidiomycetous yeasts distinguished by their mucoid colonies and vibrant carotenoid pigmentation, includes eight species. Among them, R. mucilaginosa, R. glutinis, and R. minuta are associated with the human body, with R. mucilaginosa being the most prevalent, followed by R. glutinis (Wirth and Goldani 2012). Rhodotorula mucilaginosa is widely distributed in nature and considered a component of the healthy human microbiome, inhabiting the skin, nails, and mucosal surfaces of the respiratory and gastrointestinal tracts (Wirth and Goldani 2012, Findley et al. 2013). Within the skin mycobiome, it maintains a dynamic equilibrium with other fungi, cohabiting niches alongside dominant genera, such as Malassezia and Candida (Naik et al. 2024). However, their commensal relationship with the host is very likely conditional; when host defenses are weakened, or the skin barrier is breached, R. mucilaginosa can act as a pathogen, a transition particularly common in patients with indwelling medical devices (Cosio et al. 2021). Therefore, R. mucilaginosa is best viewed as a skin-associated colonizer with opportunistic pathogenic potential, rather than as a primary cutaneous fungal pathogen. Given this dual identity, understanding iron uptake in R. mucilaginosa is important for not only defining its basic physiology but also clarifying how it persists on human skin and under what conditions it may transition from being a harmless commensal to a clinically relevant pathogen.

Like other human skin-associated fungi, R. mucilaginosa must survive in an environment where freely available iron is extremely limited. Although the iron uptake systems of R. mucilaginosa have been studied far less extensively than those of major fungal pathogens, such as C. albicans, one study reported that R. mucilaginosa produces the siderophore rhodotorulic acid when grown in iron-restricted medium and that the fungus’s growth kinetics are influenced by iron availability, providing strong evidence that siderophore-mediated iron scavenging is a central response of this yeast to iron starvation (Andersen et al. 2003). Additionally, these observations suggest that iron scavenging significantly contributes to the survival and persistence of R. mucilaginosa in the nutrient- and iron-limited environment of human skin.

Rhodotorulic acid is a hydroxamate siderophore and one of the classical iron-chelating metabolites described in basidiomycetous yeasts (Atkin et al. 1970). A study focusing on the mechanisms of iron uptake in R. pilimanae found that rhodotorulic acid facilitates iron delivery to the cell surface, without the siderophore being taken up intact along with the ferric ion (Carrano and Raymond 1978). In this process, ferric iron bound to rhodotorulic acid is transferred at the cell surface to a membrane-associated acceptor or transport system. Although this mechanism has not been demonstrated directly in R. mucilaginosa, it is reasonable to believe that rhodotorulic acid functions similarly in this species (Carrano and Raymond 1978). Siderophore-based acquisition may be particularly advantageous for R. mucilaginosa in the skin environment. Secreted siderophores like rhodotorulic acid allow the fungus to chelate trace ferric iron in the extracellular milieu and compete effectively with cohabiting microbes. Apart from siderophore-mediated iron utilization, no studies have directly identified or characterized reductive high-affinity iron uptake systems based on ferric reductases, ferroxidases, and iron permeases in R. mucilaginosa.

Dermatophytes

Dermatophytes, such as Trichophyton rubrum, T. mentagrophytes, T. tonsurans, and Microsporum species, colonize keratinized tissues, including the stratum corneum, hair, and nails, where freely available iron is scarce. Early studies of dermatophytes showed they possess specific requirements for iron to sustain growth beyond the initial stages of the germ tube formation (Artis et al. 1983). When T. mentagrophytes is cultured in the presence of iron chelating agents, growth is significantly inhibited, and the addition of ferric iron completely restores growth, whereas other transition metals, such as zinc, copper, and manganese, fail to (Artis et al. 1983). Similarly, deferoxamine methanesulfonate, a xenosiderophore, inhibits germ tube formation and hyphal elongation in T. mentagrophytes. Again, this growth inhibition is strictly due to iron deprivation, as simultaneously supplying iron counteracts the fungistatic effects of deferoxamine (Kerbs et al. 1979).

Another study demonstrated that unsaturated transferrin is largely responsible for the inhibitory activity of serum on a range of dermatophytes, including Trichophyton, Microsporium, and Epidermophyton species. The growth inhibition of the dermatophytes was correlated with unsaturated transferrin levels in human serum and neutralized by iron additions, with growth inhibition restored by adding purified iron-free transferrin. These findings suggest that dermatophytes encounter host-derived iron-binding proteins, such as transferrin, under inflammation, in damaged tissues, or during deeper invasion, and must compete with host nutritional immunity for iron acquisition (King et al. 1975). Following this, an additional study using a fluorescently labeled protein showed that transferrin directly binds to the surface of T. mentagrophyte. It is hypothesized that transferrin may inhibit the growth of the fungus through a direct interaction with the fungal cell wall, possibly by forming a mixed ligand complex with cell wall-bound hydroxamate siderophores secreted by the fungus (Artis et al. 1983, Holzberg and Artis 1983).

Dermatophytes require iron for growth, but aside from those used in siderophore-mediated iron uptake, the components of their iron acquisition systems have not been explored. Microsporum gypseum was shown to produce two siderophores under iron-deficient conditions, and the principal one was identified as a hydroxamate-type siderophore, ferricrocin, using biochemical and spectroscopic methods (Bentley et al. 1986). A comparative study reported that under low-iron conditions, M. gypseum, M. canis, M. audouinii, and T. rubrum produce ferrichrome C and ferricrocin, while T. mentagrophytes and T. tonsurans produce ferrichrome (Henia Mor et al. 1992). This suggests that dermatophytes commonly release ferrichrome-type siderophores into the extracellular environment to chelate ferric iron and then uptake siderophore-bound iron through yet unknown systems. The contribution of ferricrocin to extracellular iron acquisition is likely minimal compared with that of canonical extracellular siderophores, as ferricrocin is generally considered an intracellular siderophore involved in iron storage and intracellular iron distribution. However, recent evidence observed in A. fumigatus suggests that ferricrocin can also be secreted and contribute to iron acquisition during germination (Eisendle et al. 2006, Schrettl et al. 2007, Happacher et al. 2023). In the skin, the siderophore-dependent acquisition strategy is likely highly relevant in iron-poor keratinized tissue, where soluble iron is rare, and most is bound to host proteins. It should be noted that dermatophytes also secrete keratin- and elastin-degrading proteases during skin invasion, and these proteases may indirectly increase access to host nutrients, including iron-containing or iron-binding molecules, by degrading epidermal matrix components (Kaufman et al. 2007).

Concluding remarks

Overall, the studies summarized above suggest that skin-associated fungi rely on a diverse range of iron acquisition mechanisms, including the reductive iron uptake, heme and ferritin utilization, and siderophore-mediated iron scavenging, but the full picture is still incomplete (Table 1). Among skin-associated fungi, iron acquisition mechanisms have been defined in detail in only a few fungi. In C. albicans, iron uptake systems are well-characterized, but their direct contribution to cutaneous colonization and pathogenicity remains insufficiently understood. In C. auris, persistent skin colonization is a critical biological characteristic. However, the specific iron sources and uptake pathways that support C. auris’ survival on human skin remain largely unresolved. Rhodotorula mucilaginosa and dermatophytes provide clearer examples of siderophore-associated iron acquisition, but the relevant transporters and regulatory networks and their contributions to virulence are still poorly characterized. Most notably, although Malassezia species dominate the human skin mycobiome, their iron acquisition strategies remain almost completely unexplored.

Table 1.

Summary of iron acquisition mechanisms in major skin-associated fungi.

Fungal species	Primary and potential iron sources	Characterized/putative acquisition mechanisms	Key references
Candida albicans	Free iron, heme, ferritin, transferrin, and xenosiderophores	Reductive iron uptake (characterized): FRE10, FRE7, FRP1, FRP2, FET34, and FTR1 Heme/hemoglobin utilization (characterized): RBT5, PGA7, CSA2, and HMX1 Ferritin uptake (characterized): ALS3 (hypha-associated) Xenosiderophore uptake (characterized): SIT1/ARN1	(Ramanan and Wang 2000, Heymann et al. 2002, Weissman and Kornitzer 2004, Pendrak et al. 2004, Knight et al. 2005, Baek et al. 2008, Almeida et al. 2008, Jeeves et al. 2011, Ziegler et al. 2011, Kuznets et al. 2014, Roy and Kornitzer 2019, Weissman et al. 2021, Fu et al. 2026)
Candida auris	Heme (putative), transferrin, and xenosiderophores	Reductive iron uptake (putative): homologs of FTR1 and FET3 (FRP2 homolog absent) Heme utilization (putative): hemolytic activity observed; direct uptake unconfirmed Ferritin uptake: not characterized but biologically plausible Siderophore uptake (putative): upregulation of XTC genes demonstrated	(Kumar et al. 2015, Simm et al. 2022, Roy et al. 2022, Wang et al. 2024, Gifford et al. 2025, Brouwer et al. 2025, de-la-Fuente et al. 2025)
Dermatophytes Trichophyton rubrum, T. mentagrophytes, Microsporum gypseum, etc.	Host iron-binding proteins (transferrin), siderophores	Reductive/heme/ferritin pathways: not characterized Siderophore secretion (characterized): ferrichrome, ferrichrome C, and ferricrocin (hydroxamate-type)	(Artis et al. 1983 (x2); King et al. 1975, Kerbs et al. 1979, Holzberg and Artis 1983, Bentley et al. 1986; Henia Mor et al. 1992, Kaufman et al. 2007)
Rhodotorula mucilaginosa	Siderophores	Reductive/heme/ferritin pathways: not characterized Siderophore secretion (characterized): rhodotorulic acid (hydroxamate-type) induced under iron restriction	(Atkin et al. 1970, Carrano and Raymond 1978, Andersen et al. 2003)
Malassezia species M. restricta, M. globosa, etc.	Unknown; growth inhibited by transferrin; no known transferrin/lactoferrin receptors identified	Reductive/heme/ferritin/siderophore pathways: not characterized; genomic surveys for FTR1/FET3, CFEM-domain, and NRPS-type siderophore gene homologs have not been performed and should be a priority for future work	(Bond et al. 2005, Xu et al. 2007, Wu et al. 2015, Park et al. 2018, Ianiri et al. 2020, Brouwer et al. 2024; Vijaya Chandra et al. 2020)

^*For each species, mechanisms are labeled as “characterized” (directly demonstrated experimentally) or “putative” (inferred from genomic homology, indirect phenotypes, or extrapolation from related species); “not characterized” indicates that no dedicated study has addressed it in the corresponding fungal species. See main text for full descriptions.

Consequently, future studies should focus more on how fungi utilize iron in skin-specific environments, rather than relying on standard systemic or mucosal infection models. These skin-relevant models must accurately mimic the actual pH, lipid composition, and unique nutritional immunity of human skin. Furthermore, the role of polymicrobial interactions among skin-associated fungi in the context of iron acquisition should be considered, because skin fungi coexist with bacteria and other fungi that may compete for iron or provide xenosiderophores.

Future research directly comparing iron acquisition and iron-responsive gene expression between the commensal and pathogenic states in relevant fungi is also warranted. Given that iron availability influences virulence in many fungal pathogens (Noble 2013) and that species such as Malassezia and C. albicans both commonly colonize healthy skin while also contributing to specific cutaneous and systemic diseases (Kumamoto et al. 2020, Vijaya Chandra et al. 2020), determining whether specialized iron acquisition mechanisms are a constitutive feature of skin colonization or, instead, specifically upregulated during the transition to pathogenicity would link them to disease outcomes.

Conflicts of interest

None declared.

Funding

This work was supported by a Chung-Ang University research grant in 2025, a National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2025-23524442), and a National Institute of Health (NIH) research project (project No. #2024ER210600).