METTL4 regulates synaptic UCP2 N6-adenosine methylation to mediate pain hypersensitivity in female mice

Epitranscriptomics modifications play an important role in sex-dependent biological phenomena. N6-adenosine methylation (m6A), the most prevalent epitranscriptomics modification in eukaryotic mRNA, participates in regulating various sex-specific physiological processes. Here, we generated METTL4 knockout mice lacking methyltransferase-like 4, which mediates m6A. Behavioral analyses revealed that only female METTL4^-/- mice exhibited pain hypersensitivity, with subsequent experiments showing the involvement of METTL4-mediated m6A in this sex-differentiated biological phenotype. Further exploration demonstrated that this sex-specific pain hypersensitivity is closely associated with sex-dependent expression of uncoupling protein 2 (UCP2) in synapses. Specifically, elevated UCP2 expression in METTL4^-/- female mice enhances the efficiency of synaptic transmission by modulating mitochondrial energy metabolism at synapses. Collectively, this study identifies a distinct pathway mediated by METTL4-driven m6A modification, providing critical insights into the molecular basis of sex-specific differences in pain transmission. These findings also highlight the potential of targeting METTL4 for sex-differentiated pain management strategies in clinical settings.