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The heart is known for its high lipid content, and disorders or abnormalities in lipid metabolism are frequently associated with cardiovascular diseases. This study aimed to investigate the regulatory roles of lipids in AF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Using tree-based ensemble learning-assisted lipidomics, sphingomyelin was identified as a key differential metabolite and found to be significantly reduced in AF patients. Exogenous supplementation of sphingomyelin significantly attenuated acetylcholine\u2013CaCl2-induced and angiotensin II-induced AF, fibrosis, and inflammation in mice. Furthermore, decreased sphingomyelin levels were attributed to increased activity of sphingomyelin phosphodiesterases (SMPDs) under AF conditions. Mechanistically, RNA-Seq analysis demonstrated that sphingomyelin inhibits AF-induced activation of the Rap1 signalling pathway, a finding corroborated by overexpression and knockdown of RAP1 in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Together, these findings highlight the therapeutic potential of sphingomyelin and SMPD inhibitors in mitigating AF through inhibition of the Rap1 signalling pathway, thereby establishing the targeting of sphingomyelin metabolism as a viable and novel treatment strategy for AF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/europace\/euag270","type":"journal-article","created":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T11:38:55Z","timestamp":1789817935000},"source":"Crossref","is-referenced-by-count":0,"title":["Sphingomyelin as a key negative mediator in atrial fibrillation\n                    <i>via<\/i>\n     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