{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T05:17:21Z","timestamp":1788585441085,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017536","name":"Shanghai Pulmonary Hospital","doi-asserted-by":"crossref","award":["fkzr2568"],"award-info":[{"award-number":["fkzr2568"]}],"id":[{"id":"10.13039\/501100017536","id-type":"DOI","asserted-by":"crossref"}]},{"award":["fkzr2568"],"award-info":[{"award-number":["fkzr2568"]}],"id":[{"id":"https:\/\/ror.org\/033nbnf69","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Non-small-cell lung cancer (NSCLC) treatment is hampered by its complex pathogenesis and high heterogeneity. N6-methyladenosine (m6A) represents the most common post-transcriptional modification regulating RNA stability and function in eukaryotes. This methylation is catalyzed by methyltransferase complexes, with METTL14 being the core catalytic subunit. Abnormal expression of lncRNA MSTRG.292666.16 is related to poor prognosis of NSCLC. However, the mechanism by which it regulates NSCLC progression through m6A modification remains unclear. We employed cell function experiments, molecular mechanism analysis, RNA interaction experiments, and a nude mouse tumor model to explore the roles of METTL14-mediated MSTRG.292666.16 m6A modification in NSCLC and the potential MAPK signaling pathway involved. METTL14 was significantly upregulated in NSCLC cell lines and promoted m6A modification of MSTRG.292666.16 by forming a stable association with it. METTL14 knockdown significantly inhibited the viability, migration and invasion of A549 cells and promoted apoptosis, whereas MSTRG.292666.16 overexpression reversed these effects. Mechanistically, METTL14 upregulated the expression of MSTRG.292666.16 through m6A modification, thereby activating the MAPK pathway (manifested as elevated levels of MAPK8IP3 and p-ERK1\/2). The use of a selective p38 MAPK inhibitor SB203580 stimulated the tumor-suppressive effect of METTL14 knockdown, whereas the activator U-46619 reversed it. In vivo experiments confirmed that METTL14 knockdown significantly inhibited tumor growth, whereas MSTRG.292666.16 overexpression partially restored the malignant phenotype of the tumor, which was associated with MAPK pathway activation. This study revealed that METTL14-dependent m6A modification of MSTRG.292666.16 may act as an upstream driver to activate the MAPK cascade and facilitate NSCLC progression. These findings clarify a key epitranscriptomic regulatory mechanism driving NSCLC development and offer preliminary molecular clues for exploring potential therapeutic targets in subsequent clinical NSCLC research.<\/jats:p>","DOI":"10.3390\/ijms27177868","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:10:33Z","timestamp":1788430233000},"page":"7868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["METTL14-Mediated lncRNA MSTRG.292666.16 m6A Modification Promotes the Progression of Non-Small-Cell Lung Cancer Through the MAPK Pathway"],"prefix":"10.3390","volume":"27","author":[{"given":"Qinfang","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heyong","family":"Wang","sequence":"additional","affiliation":[{"name":"Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenlei","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianxiu","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyu","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boxiong","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Thoracic, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songwen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.6004\/jnccn.2204.0023","article-title":"Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology","volume":"22","author":"Riely","year":"2024","journal-title":"J. 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