{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T05:19:09Z","timestamp":1787548749396,"version":"build-2736575974"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Acute myocarditis is a non-ischemic cardiomyopathy with rapid onset and high mortality. Immunometabolic reprogramming of macrophages is a key pathological feature. However the understanding of its mechanisms remains to be clarified. In this study, we found that acute myocarditis induced an increase in glycolysis and lactate accumulation. Inhibition of lactate production ameliorated myocardial injury. Further, we demonstrated that lactate promoted a pro-inflammatory transition of macrophages, thereby amplifying the inflammatory response. Inhibition of lactate in macrophage shifted its phenotype from a pro-inflammatory to an anti-inflammatory subtype. We also observed a significant increase in H4K5 lactylation in macrophages. Next, we identified that H4K5la drove the transcriptional expression of the Rap1, which in turn upregulated the TNF\/NF-\u03baB signaling. This lactate-dependent H4K5la was enriched in inflammatory pathways, forming a positive feedback loop that amplified inflammation. Inhibition of Rap1 reduced cardiac inflammation and broke this loop. These consequently lowered H4K5la levels and delayed ventricular remodeling. Collectively, this study reveals the role of H4K5la in promoting inflammatory cascades in myocarditis, and provides a potential therapeutic target for inflammatory cardiomyopathy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1896701","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T04:24:39Z","timestamp":1787545479000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["H4K5 lactylation exacerbates acute myocarditis by driving a positive feedback loop between inflammation and metabolic dysfunction"],"prefix":"10.3389","volume":"17","author":[{"given":"Yawei","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Cardiology, Cardiovascular Disease Center, Jiangsu Key Laboratory for Cardiovascular Information and Health Engineering Medicine, Nanjing Drum Tower Hospital, Medical School, Nanjing University","place":["Nanjing, 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