Mettl3-mediated m6A disruption of olfactory bulb glutamatergic metabolism homeostasis via the Wnt pathway in aging leads to olfactory dysfunction.

Olfactory dysfunction not only diminishes quality of life but also serves as an early biomarker for neurodegenerative diseases. However, the molecular mechanisms underlying age-related olfactory dysfunction remain poorly understood. In this study, we profiled the dynamics of m(6)A epitranscriptomics in mouse olfactory bulbs (OBs) throughout postnatal development, adulthood, and aging, revealing the dynamic remodeling of m(6)A methylation during the aging process. Our findings indicate that m(6)A modifications regulate various physiological processes in a stage-specific manner. Notably, in aged OBs, m(6)A methylation is enriched in genes associated with the Wnt signaling pathway. Furthermore, we identified a Wnt pathway involving Wnt, Ror2, and Nkd1 that may contribute to disrupted glutamate metabolism responses linked to age-related alterations in glutamatergic neuron function. This disruption is accompanied by significant reductions in glutamate and its related metabolites, suggesting an imbalance in neurotransmitter levels and impaired mitochondrial function—factors that may lead to olfactory dysfunction. Additionally, we identified METTL3 as a key m(6)A methyltransferase that drives age-related declines in olfactory function. Conditional knockdown of Mettl3 in aged OBs restores both olfactory function and activity within glutamatergic neurons. Our study provides valuable insights into the m(6)A-mediated mechanisms governing OB aging and highlights potential therapeutic targets for mitigating neur odegenerative-associated olfactory deficits. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-025-06069-x.