Gastrodin regulates H3K14la through the CDT2-KAT2A axis to treat Sepsis-induced myocardial dysfunction.

Sepsis-induced myocardial dysfunction (SIMD), a life-threatening complication of systemic infection, lacks effective therapies. This study investigated whether Gastrodin (GAS) alleviates SIMD by modulating ubiquitination and histone lactylation pathways. Using an in vivo lipopolysaccharide (LPS)-induced murine model and in vitro TNF-α-stimulated human cardiomyocytes (AC16), we evaluated the effects of GAS on myocardial injury, inflammation, and apoptosis. GAS treatment significantly reduced myocardial damage, serum cardiac injury markers (cTnT, CK-MB), and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in mice. Transcriptomic analysis also enriched for inflammatory and apoptotic pathways. In vitro, GAS protected AC16 cells from TNF-α-induced apoptosis and suppressed glycolysis-derived lactate accumulation. Mechanistically, GAS enhanced CDT2-KAT2A binding, promoting ubiquitin-mediated KAT2A degradation, which reduced histone H3 lysine 14 lactylation (H3K14la) and restored energy metabolism. Multi-omics integration confirmed the role of GAS in glycolytic inhibition and lactylation modulation. These findings demonstrated that GAS ameliorates SIMD by targeting the CDT2-KAT2A axis to regulate ubiquitination-lactylation, providing novel therapeutic insights for septic cardiomyopathy.