{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:16:04Z","timestamp":1789154164715,"version":"build-2803163510"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T00:00:00Z","timestamp":1749168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>As the most abundant epitranscriptomic modification, N6-methyladenosine (m6A) critically influences aging and age-related pathologies. However, its regulatory interplay with microRNAs (miRNAs) in skin aging remains poorly defined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Aging phenotypes were recapitulated using D-galactose (D-gal)-induced senescence models in mouse skin fibroblasts (MSFs) and mice. Interventions included METTL3 overexpression\/knockdown, miR-208a-5p mimic\/inhibitor transfection, and pharmacological mitophagy induction (GSK).\u00a0Molecular analyses assessed m\u2076A dynamics, gene regulation, and mitochondrial function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In D-gal-induced aging models, global RNA hypomethylation and reduced METTL3 expression were observed, while METTL3 overexpression attenuated cellular senescence. Mechanistically, METTL3 depletion elevated miR-208a-5p levels via YTHDF2-mediated m\u2076A recognition, establishing epitranscriptional control. This upregulated miR-208a-5p directly targeted the 3'-UTR of OPA1 (optic atrophy type 1), suppressing mitophagic activity. Critically, senescent phenotypes induced by METTL3 knockdown or miR-208a-5p mimicry were reversed by pharmacological mitophagy induction (GSK), confirming mitochondrial homeostasis as the pathway's functional nexus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These results establish an m6A-dependent METTL3\/miR-208a-5p\/OPA1 axis that regulates mitophagy and skin aging. Pharmacological rescue of mitophagy highlights this pathway's therapeutic relevance for age-related dermatopathology.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1577783","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T04:10:50Z","timestamp":1749183050000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["METTL3-mediated m6A modification regulates D-galactose-induced skin fibroblast senescence through 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