Jaceosidin Attenuates Sepsis-Induced Myocardial Dysfunction by Promoting SIRT2-Mediated Inhibition of Histone H3K18 Lactylation

TL;DR

Jaceosidin protects against sepsis-induced heart damage by inhibiting a specific histone modification through SIRT2 activation.

Contribution

Jaceosidin is identified as a novel metabolic-epigenetic therapeutic for sepsis-induced myocardial dysfunction.

Findings

Jaceosidin reduces cardiomyocyte injury and apoptosis in vitro.

Jaceosidin inhibits histone H3K18 lactylation via SIRT2 activation.

Jaceosidin improves cardiac function and reduces inflammation in a murine sepsis model.

Abstract

Background: Sepsis-induced myocardial dysfunction (SIMD) is a life-threatening complication with limited therapeutic options. Jaceosidin (JAC), a natural flavonoid from Folium Artemisiae Argyi, shows potential in cardiovascular diseases, but its role and mechanism in SIMD remain unclear. This study aims to investigate the protective effects of JAC against SIMD and explore the underlying molecular mechanisms. Methods: In vitro, AC16 human cardiomyocytes were stimulated with TNF-α and treated with JAC. Cell viability and apoptosis were assessed using CCK−8 and flow cytometry, respectively. Transcriptomic and metabolomic analyses were performed to identify altered pathways. Molecular docking evaluated JAC’s interaction with SIRT2. The SIRT2 inhibitor AGK2 was used to validate its role. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) determined H3K18la enrichment on target gene promoters. In vivo, a murine SIMD model was established via LPS injection, and cardiac function was evaluated by echocardiography. Serum markers (cTnT, CK−MB) and myocardial lactylation levels were measured. Results: JAC significantly attenuated TNF-α−induced injury in AC16 cells by enhancing viability and reducing apoptosis. Multi-omics analyses revealed JAC suppressed glycolysis and lactate production. JAC specifically inhibited histone H3K18 lactylation (H3K18la), and molecular docking indicated strong binding affinity with SIRT2. AGK2 treatment reversed JAC-mediated suppression of H3K18la. ChIP-qPCR confirmed H3K18la directly regulates IL-6, BAX, and BCL-2 expression. In vivo, JAC improved cardiac function (LVEF, LVFS, LVDd, LVDs), reduced serum cTnT and CK−MB levels, and decreased myocardial H3K18la in LPS−treated mice. Conclusions: JAC alleviates SIMD by activating SIRT2, which inhibits H3K18la, thereby modulating inflammatory and apoptotic pathways. This study identifies JAC as a novel metabolic-epigenetic therapeutic agent for SIMD.

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