METTL9 is a protein-histidine N-methyltransferase that catalyzes 1-methylhistidine modification of target proteins containing a His-x-His (HxH) motif, where x is preferably a small amino acid [33563959]. The enzyme specifically methylates the second histidine while using the first as a recognition signature [37398635], and constitutes the main methyltransferase for 1-methylhistidine modification in cells. Identified substrates include S100A9, NDUFB3, SLC39A5, SLC39A7, ARMC6, and DNAJB12; methylation may modulate zinc and metal binding to these proteins [33563959, 34562450, 37015930, 37398635]. Beyond its catalytic role, METTL9 sustains vertebrate neural development primarily through non-catalytic functions involving maintenance of the secretory pathway and Golgi integrity [40745158]. Recent evidence suggests distinct disease relevance across contexts: in osteoporosis, METTL9-mediated methylation of SLC39A7 suppresses ferroptosis and inhibits adipogenic differentiation of mesenchymal stem cells, with METTL9 overexpression alleviating bone loss in ovariectomy model mice [40414869]. In cancer, elevated METTL9 associates with peritoneal dissemination in gastric cancer through mitochondrial Complex I modulation [35402738], while the circular RNA derived from METTL9 promotes colorectal cancer progression via the miR-551b-5p/CDK6 axis [37158456]. Additionally, intestinal epithelial cells secrete METTL9 as a catalytic antifungal effector, methylating the fungal zinc-scavenging protein PRA1 to restrict Candida colonization; reduced METTL9 in inflammatory bowel disease correlates with increased fungal abundance [41412125].