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Dihydromyricetin (DMY), a flavonoid derived from Vine tea, has shown cardioprotective effects, but its mechanism of action in MIRI is not fully understood. This study aimed to investigate the therapeutic effects of DMY on MIRI and elucidate the underlying molecular mechanisms. A rat model of MIRI was established by left anterior descending coronary artery ligation. Rats received DMY or the positive control diltiazem (DIL) for 7\u2009days post\u2010injury. Cardiac damage was assessed by measuring cardiac troponin levels and histopathological analysis. The expression of chemokine\u2010like factor 1 (CKLF1) and its downstream signaling pathways was examined using molecular and biochemical approaches. The interaction between DMY and CKLF1 was further validated using a CKLF1 agonist (C27) and CKLF1\u2010knockout rats. CKLF1 expression was significantly upregulated in MIRI, correlating with inflammatory infiltration, tissue disorganization, and elevated cardiac troponin levels. Mechanistically, CKLF1 activation promoted phosphorylation of nuclear factor kappa\u2010B (NF\u2010\u03baB) and subsequent assembly of the NLR family pyrin domain\u2010containing 3 (NLRP3) inflammasome, leading to caspase\u20101\u2010dependent pyroptosis. DMY treatment attenuated these effects by downregulating CKLF1 expression and disrupting its interaction with C\u2010C chemokine receptor type 5 (CCR5) and NLRP3, thereby suppressing pyroptosis. Notably, activation of CKLF1 signaling by its agonist C27 reversed the protective effects of DMY. Moreover, while CKLF1 knockout modestly reduced pyroptosis\u2010related protein expression, the anti\u2010pyroptotic effect of DMY was abolished in knockout rats, indicating its dependence on CKLF1. These findings demonstrate that DMY alleviates MIRI by targeting the CKLF1\/NF\u2010\u03baB\/NLRP3 axis, thereby inhibiting pyroptosis and preserving cardiomyocyte integrity. The anti\u2010pyroptotic effect of DMY is specifically dependent on CKLF1 expression. This study provides a novel mechanistic basis for developing targeted therapies against MIRI.<\/jats:p>","DOI":"10.1002\/ptr.70364","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T13:08:00Z","timestamp":1780060080000},"page":"5277-5298","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dihydromyricetin Ameliorates Myocardial Ischemia\u2013Reperfusion Injury by Modulating\n                    <scp>CKLF1<\/scp>\n                    \u2010Mediated Cardiomyocyte Pyroptosis"],"prefix":"10.1002","volume":"40","author":[{"given":"Yuting","family":"Lin","sequence":"first","affiliation":[{"name":"Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, College of Pharmacy, Hunan University of Chinese Medicine  Changsha 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