ORIGINAL RESEARCH article

Front. Immunol.

Sec. Inflammation

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1577783

This article is part of the Research TopicImmunosenescence and Inflammaging: Modulating Immune Function through Diet, Lifestyle, and Therapeutic InterventionsView all articles

METTL3-Mediated m6A Modification Regulates D-galactose-induced Skin Fibroblast Senescence Through miR-208a-5p

Provisionally accepted
Gaoxiang HuangGaoxiang Huang1Sainan SunSainan Sun2Mingde LiaoMingde Liao3Jing WangJing Wang2Qing YanQing Yan2Jing LiJing Li2Yi MengYi Meng4Qi WangQi Wang2Zhen GuoZhen Guo2Jiyong TanJiyong Tan2Jing LiJing Li2*
  • 1Central People’s Hospital of Zhanjiang, Zhanjiang, China
  • 2School of Basic Medicine, Guangxi Medical University, Nanning, Guangxi Zhuang Region, China
  • 3First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi Zhuang Region, China
  • 4Guangxi Medical University, Nanning, Guangxi Zhuang Region, China

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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. Here, we employed D-galactose (D-gal)-induced senescence models in mouse skin fibroblasts (MSFs) and mice, which recapitulated aging phenotypes marked by global RNA hypomethylation and reduced expression of the methyltransferase METTL3. Strikingly, METTL3 overexpression attenuated senescence, highlighting its protective role in aging regulation. Mechanistically, METTL3 depletion upregulated mature miR-208a-5p expression in an m6A-dependent manner via the m6A reader YTHDF2. Functional studies revealed that miR-208a-5p directly targets the 3'-untranslated region (3'-UTR) of optic atrophy type 1 (OPA1) mRNA, a key mediator of mitochondrial fusion, leading to suppressed mitophagic activity. Importantly, the prosenescent effects of METTL3 knockdown and miR-208a-5p mimic were reversed by pharmacological induction of mitophagy using GSK, underscoring the pathway's centrality in aging.

Keywords: Aging, M6A, METTL3, miR-208a-5p, senescence

Received: 16 Feb 2025; Accepted: 21 May 2025.

Copyright: © 2025 Huang, Sun, Liao, Wang, Yan, Li, Meng, Wang, Guo, Tan and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Jing Li, School of Basic Medicine, Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Region, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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