AUTHOR=Huang Gaoxiang , Sun Sainan , Liao Mingde , Wang Jing , Yan Qing , Li Jing , Meng Yi , Wang Qi , Guo Zhen , Tan Jiyong , Li Jing 

TITLE=METTL3-mediated m6A modification regulates D-galactose-induced skin fibroblast senescence through miR-208a-5p

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1577783

DOI=10.3389/fimmu.2025.1577783

ISSN=1664-3224

ABSTRACT=IntroductionAs 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.MethodsAging 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). Molecular analyses assessed m⁶A dynamics, gene regulation, and mitochondrial function.ResultsIn 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 m⁶A 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.DiscussionThese 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.