The skin commensal yeast Malassezia promotes tissue homeostasis via the aryl hydrocarbon receptor

ABSTRACT As an abundant fungal colonizer of human skin, Malassezia has long been associated with pathological skin conditions, yet its role in skin homeostasis remain poorly understood. Here, we demonstrate that Malassezia furfur plays an active role in maintaining epidermal integrity by producing tryptophan-derived metabolites that activate the aryl hydrocarbon receptor (AhR), a key regulator of keratinocyte differentiation and inflammation. Using a fungal mutant defective in indole production, we show that M. furfur-derived AhR activation is required to restore barrier function and control inflammation in diseased skin. AhR-deficient mice fail to benefit from M. furfur-mediated barrier protection, underscoring the importance of microbial-derived AhR agonists in skin physiology. These findings establish a previously unrecognized mutualistic role for Malassezia in epidermal homeostasis, challenging its perception as solely a pathogenic fungus and expanding our understanding of the skin microbiota’s influence on barrier function and immune regulation. KEY FINDINGS Malassezia-derived indoles reprogram epidermal gene expression to enhance keratinocyte function. AhR activation by Malassezia restores skin barrier integrity and reduces inflammation. Malassezia Sul1-dependent tryptophan metabolism is essential for the production of AhR agonists. The barrier protective effects of Malassezia are mediated specifically through keratinocyte intrinsic AhR signaling. Competing Interest Statement The authors have declared no competing interest.