METTL18 is Required for Developmental, Metabolic, and Endocrine Regulation of Mammalian Growth

Histidine methylation is an evolutionarily conserved but poorly understood post‐translational modification. METTL18 is known to catalyze histidine N τ‐methylation in vitro, yet its physiological functions in mammals remain unclear. Here we show that mouse METTL18 possesses conserved histidine N τ‐methyltransferase activity and that its genetic deletion results in widespread effects on developmental, metabolic, and endocrine function. Mettl18 knockout (KO) embryos exhibit impaired growth with disruption of the transferrin–transferrin receptor (Trf–Tfrc) axis, suggesting insufficient fetal iron handling. After birth, Mettl18 KO mice remain underweight and show reduced liver and white adipose tissue mass. Moreover, Mettl18 KO mice exhibit decreased plasma and liver triglycerides, elevated adiponectin and improved glucose tolerance, indicative of a coordinated shift toward an energy‐conserving metabolic Trf–Tfrc state. Notably, METTL18 deficiency impairs IGF‐1‐mediated signaling and suppresses the TSH–T4 axis, two major endocrine pathways critical for postnatal growth. Taken together, our results indicate that METTL18 functions as a conserved histidine methyltransferase that contributes to fetal development, endocrine regulation, and systemic metabolism, thereby influencing organismal growth in mammals.