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Neohesperidin, a flavonoid in citrus fruits, has various health benefits. The aim of this study was to explore the cardioprotective effects and mechanisms of neohesperidin against DOX\u2010induced cardiotoxicity (DIC). The study used DOX\u2010treated mice to evaluate cardiac function and cardiomyocyte injury. In addition, primary cardiomyocytes treated with DOX were used to measure cell viability and death. FIN56, a ferroptosis inhibitor, was used to test the relationship between neohesperidin's beneficial effect and ferroptosis. Mechanistic investigations were carried out to explore the role of N6\u2010methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) levels, nuclear factor erythroid\u20102\u2010related factor 2 (Nrf2) expression, and Methyltransferase\u2010like 3 (Mettl3) in the cardioprotective effect of neohesperidin. Overexpression and knockdown of Mettl3 were also performed to confirm its role in the cardioprotective effect. Neohesperidin attenuated cardiac function and cardiomyocyte injury in DOX\u2010treated mice. It alleviated DOX\u2010induced oxidative stress by reducing reactive oxygen species and malondialdehyde levels and increasing superoxide dismutase and glutathione levels, restoring ATP production. In DOX\u2010treated primary cardiomyocytes, neohesperidin increased cell viability and decreased cell death. FIN56 abolished the beneficial effect of neohesperidin. Mechanistically, neohesperidin decreased m\n                    <jats:sup>6<\/jats:sup>\n                    A levels, leading to increased Nrf2 expression. Nrf2 activation was related to the inhibition of Mettl3, an m\n                    <jats:sup>6<\/jats:sup>\n                    A \u201cwriter,\u201d which protected cardiomyocytes against DOX\u2010induced ferroptosis. Overexpressing Mettl3 reversed the cardioprotective effects of neohesperidin and diminished its benefits on ferroptosis. These findings suggest that neohesperidin exerts a cardioprotective effect against DIC by inhibiting ferroptosis. This effect is achieved by regulating the Mettl3\u2010m\n                    <jats:sup>6<\/jats:sup>\n                    A\u2010Nrf2 signaling pathway, indicating the therapeutic potential of neohesperidin.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70458","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:10:14Z","timestamp":1790205014000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neohesperidin Alleviates Ferroptosis in Doxorubicin\u2010Induced Cardiotoxicity via Mettl3\u2010\n                    <scp>\n                      m\n                      <sup>6<\/sup>\n                      A\n                    <\/scp>\n                    \u2010Nrf2 Signaling"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2687-596X","authenticated-orcid":false,"given":"Ruijia","family":"Wen","sequence":"first","affiliation":[{"name":"Guangzhou University 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