Eupatilin Ameliorates Sepsis‐Induced Myocardial Injury by Targeting the KAT5 ‐ H3K27la Epigenetic Axis

Sepsis induced myocardial injury (SIMI) remains a life threatening complication with mortality rates exceeding 40% to 50%, yet effective therapies are lacking. This study investigates the cardioprotective effects of eupatilin (EUP), a bioactive flavonoid derived from Artemisia argyi, and reveals a previously unrecognized mechanism involving selective modulation of KAT5 mediated histone H3K27 lactylation (H3K27la). Using an LPS induced murine model and TNF‐α stimulated human AC16 cardiomyocytes, we evaluated cardiac function, inflammatory responses, and apoptotic pathways through dose response analyses. Multi omics approaches including RNA seq, metabolomics, ChIP seq, and molecular docking were integrated to dissect the pharmacodynamic profile of EUP. EUP conferred concentration dependent cardioprotection with optimal effects at 25 μM. Compared with conventional glucocorticoid therapy, EUP showed enhanced target selectivity, markedly reducing pro inflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6 while improving cardiac function parameters including ejection fraction and fractional shortening. Mechanistically, EUP bound KAT5 with high affinity, suppressed its lactylation activity, and reduced H3K27la enrichment at the promoters of inflammatory genes. Metabolic flux analysis further indicated that EUP inhibited glycolytic lactate production and restored oxidative phosphorylation. Together, these findings identify EUP as a natural modulator of the KAT5‐H3K27la axis, addressing both metabolic dysregulation and epigenetic reprogramming in SIMI. With a favorable pharmacokinetic profile and superior target specificity relative to standard immunosuppressive regimens, EUP holds promise for clinical translation in sepsis associated cardiac dysfunction.