A gut-secreted histidine methyltransferase enforces cross-kingdom catalytic antifungal defense.

Mucosal immunity deploys diverse defenses against fungal pathogens, yet the evolution of fungal resistance demands new antifungal strategies. Here, we uncover that intestinal epithelial cells secrete the host histidine methyltransferase METTL9 as a cross-kingdom, catalytic antifungal effector. Proteomic profiling revealed that exposure to Candida albicans induces robust METTL9 secretion into the intestinal lumen. Extracellular METTL9 directly binds the fungal zinc-scavenging protein PRA1, catalyzing histidine methylation of this zincophore to disrupt zinc acquisition-an essential micronutrient for fungal growth and virulence. This methylation-driven "nutritional sabotage" restricts C. albicans colonization and dissemination in vivo and also targets multidrug-resistant Candida auris, which retains PRA1. Clinically, reduced METTL9 levels in colonic mucosa from patients with inflammatory bowel disease correlate with increased C. albicans abundance, linking METTL9 to human antifungal mucosal homeostasis. Our findings reveal a host-derived, catalytic antifungal mechanism that bypasses conventional resistance pathways, establishing secreted methyltransferases as an arm of innate mucosal immunity.