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Deregulation of <jats:italic>N<\/jats:italic><jats:sup>6<\/jats:sup>\u2010methyladenosine (m<jats:sup>6<\/jats:sup>A) modification has been identified as a key contributor to human diseases. However, the specific involvement of m<jats:sup>6<\/jats:sup>A modification in lymphatic remodeling remains poorly understood. In this study, we demonstrate that inflammatory stimulation and corneal sutures induce elevated levels of methyltransferase\u2010like 3 (METTL3)\u2010mediated m<jats:sup>6<\/jats:sup>A modification. METTL3 knockdown inhibits lymphatic endothelial viability, proliferation, migration, and tube formation in vitro. METTL3 knockdown attenuates corneal sutures\u2010induced lymphangiogenesis and intratumoral lymphangiogenesis initiated by subcutaneous grafts, consequently restraining corneal neovascularization, tumor growth, and tumor neovascularization in vivo. Mechanistically, METTL3 knockdown upregulates prostaglandin\u2013endoperoxide synthase 2 expression through an m<jats:sup>6<\/jats:sup>A\u2013YTHDF2\u2010dependent pathway, enhancing the synthesis of cyclopentenone prostaglandins (CyPGs). Aberrant CyPG production in lymphatic endothelial cells impairs mitochondrial oxidative phosphorylation, contributing to pathological lymphangiogenesis. Moreover, selective inhibition of METTL3 with STM2457 reduces m<jats:sup>6<\/jats:sup>A levels in lymphatic endothelial cells, effectively suppressing pathological lymphangiogenesis. This study provides compelling evidence that lymphatic\u2010specific METTL3 plays a critical role in vascular patterning through prostaglandin metabolism reprogramming. Thus, METTL3 emerges as a promising target for treating lymphangiogenesis\u2010related diseases.<\/jats:p>","DOI":"10.1002\/mco2.728","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T07:31:35Z","timestamp":1728027095000},"source":"Crossref","is-referenced-by-count":0,"title":["Lymphatic\u2010specific methyltransferase\u2010like 3\u2010mediated m<sup>6<\/sup>A modification drives vascular patterning through prostaglandin metabolism reprogramming"],"prefix":"10.1002","volume":"5","author":[{"given":"Lianjun","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Optometry The Affiliated Eye Hospital, Nanjing Medical University  China"},{"name":"The Fourth School of Clinical Medicine Nanjing Medical University  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuting","family":"Lu","sequence":"additional","affiliation":[{"name":"The Fourth School of Clinical Medicine Nanjing Medical 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