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Expression levels of METTL14, GPX4 and osteoclast\u2010related proteins TRAP, NFATc1, c\u2010Fos were detected by qRT\u2010PCR and Western blotting. The osteoporosis model was established in mice by bilateral ovariectomy (OVX). Bone histomorphology was determined by micro\u2010CT and H&amp;E staining. NFATc1 expression in bone tissues was determined by immunohistochemical staining. Proliferation of primary bone marrow macrophages cells (BMMs) was assessed by MTT assay. Osteoclast formation was observed by TRAP staining. The regulatory mechanism was evaluated by RNA methylation quantification assay, MeRIP\u2010qPCR, dual luciferase reporter assay, and RIP, respectively. METTL14 was down\u2010regulated in the serum samples of postmenopausal osteoporotic women, which was positively associated with bone mineral density (BMD). Osteoclast formation was promoted in OVX\u2010treated METTL14<jats:sup>+\/\u2212<\/jats:sup> mice as compared with wild\u2010type littermates. Conversely, METTL14 overexpression repressed RANKL\u2010induced osteoclast differentiation of BMMs. Mechanistically, METTL14\u2010mediated m6A modification post\u2010transcriptionally stabilized glutathione peroxidase 4 (GPX4), with the assistance of Hu\u2010Antigen R (HuR). Finally, GPX4 depletion\u2010mediated osteoclast formation in BMMs could be counteracted by METTL14 or HuR overexpression. Collectively, METTL14 inhibits osteoclastogenesis and bone resorption via enhancing GPX4 stability through an m6A\u2010HuR dependent mechanism. Therefore, targeting METTL14 might be a novel promising treatment strategy for osteoporosis.<\/jats:p>","DOI":"10.1002\/tox.23829","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T14:35:20Z","timestamp":1684334120000},"page":"2057-2068","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["<scp>METTL14<\/scp> represses osteoclast formation to ameliorate osteoporosis via enhancing <scp>GPX4 mRNA<\/scp> stability"],"prefix":"10.1002","volume":"38","author":[{"given":"Mingsi","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Stomatology The Third Xiangya Hospital of Central South University  Changsha Hunan People's Republic of China"},{"name":"Department of Orthodontics Changsha Stomatology Hospital  Changsha Hunan People's Republic of 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