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Thus, elucidating the mechanisms that regulate MSC lineage allocation is urgently needed. METTL9 was recently characterized as a novel N1-histidine methyltransferase that performs a wide range of functions. however, the role of METTL9 in the imbalance of MSC differentiation in osteoporosis remains unclear. In this study, we found that METTL9 expression was downregulated in osteoporosis, and further adipogenic functional experiments revealed that METTL9 negatively regulated the adipogenic differentiation of MSCs both in vitro and in vivo. Mechanistically, METTL9 mediated methylation of SLC39A7 at the His45 and His49 residues suppressed ferroptosis through the endoplasmic reticulum (ER) stress regulatory protein kinase R-like endoplasmic reticulum kinase (PERK)\/ATF4 signaling pathway and the downstream protein SLC7A11. Moreover, SLC7A11 transported cystine for intracellular glutathione synthesis, eliminating intracellular reactive oxygen species (ROS) and inhibiting MSC adipogenic differentiation. Additionally, METTL9 overexpression significantly alleviated bone loss in ovariectomy (OVX) model mice. In summary, our results suggest that the METTL9\/SLC39A7 axis may be a promising diagnostic and therapeutic target for osteoporosis.<\/jats:p>","DOI":"10.1186\/s10020-025-01271-w","type":"journal-article","created":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T22:19:17Z","timestamp":1748211557000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["METTL9 mediated N1-Histidine methylation of SLC39A7 confers ferroptosis resistance and inhibits adipogenic differentiation in mesenchymal stem cells"],"prefix":"10.1186","volume":"31","author":[{"given":"Jiahao","family":"Jin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanfeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangqi","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxi","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"1271_CR1","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.compbiomed.2018.07.007","volume":"100","author":"J Adulcikas","year":"2018","unstructured":"Adulcikas J, Norouzi S, Bretag L, Sohal SS, Myers S. 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All the participants provided written informed consent after receiving all the necessary information about the study\u2019s purpose, procedures, and potential risks (Clinical Ethics Approval No: 2021r209).The animal experiments were approved by the Animal Care and Use Committee of Sun Yat-sen University, Guangzhou, China, and were conducted in strict accordance with their regulations and guidelines. All the experiments in this study followed relevant ethical standards and regulatory requirements (Animal Ethics Approval No. 2021d184).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"206"}}