Sepsis-induced myocardial contractile dysfunction is one of the major causes of high mortality in septic patients, yet effective targeted therapeutic agents remain unavailable. This study aims to investigate the ameliorative effect and underlying mechanism of ginsenoside Rg5 on myocardial contractile dysfunction in sepsis.

① A mouse sepsis model was established using cecal ligation and puncture (CLP). Ninety-six male C57BL/6 mice (10 weeks old, weighing 20 to 30 g) were randomly divided into Sham group, sepsis group, and Rg5 treatment group. Cardiac function was evaluated by echocardiography. Serum cardiac troponin Ⅰ (cTnⅠ) level was detected by ELISA, and the 72-h survival rate of mice was observed. Cardiomyocytes were isolated using a Langendorff perfusion system, and their contractile function and calcium transients were subsequently detected using a cell microtensiometer. ② Network pharmacology was employed to screen the potential targets of Rg5 for the treatment of sepsis and to perform functional enrichment analysis. A protein-protein interaction (PPI) network analysis was further conducted using STRING, and hub targets were identified with Cytoscape. Western blotting was used to detect the expression of the hub target protein epidermal growth factor receptor (EGFR) across groups, and molecular docking was carried out to investigate the interaction between Rg5 and EGFR.

① Compared with the sham group, the sepsis group showed significantly reduced left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) (P<0.05), and markedly elevated levels of the myocardial injury marker cTnⅠ (P<0.05), indicating obvious myocardial dysfunction after sepsis. Rg5 treatment significantly restored myocardial function in septic mice, as evidenced by increased LVEF and LVSF values, reduced serum cTnⅠ levels, and an improved the 72-h survival rate from 25% to 50% (P<0.05). Compared with the sham group, the cardiomyocytes in the sepsis group exhibited a significantly reduced calcium transient amplitude and calcium sensitivity, along with markedly diminished contractile amplitude and slower maximal contraction and relaxation velocities (P<0.05). The treatment significantly restored calcium transient capacity in septic cardiomyocytes, ameliorated myofilament calcium desensitization, and markedly increased contractile amplitude as well as maximal contraction and relaxation velocities (P<0.05). ② Network pharmacology identified 53 potential targets of Rg5 for the treatment of sepsis. GO enrichment analysis showed that these targets were mainly involved in biological processes such as muscle cell proliferation, regulation of blood pressure, and the adenylate cyclase-activating G protein-coupled receptor signaling pathway. KEGG enrichment analysis indicated that these targets were significantly enriched in pathways related to myocardial contraction, including the calcium, Rap1, and Ras signaling pathways. PPI analysis and Cytoscape screening identified the top 10 candidate targets, including EGFR, STAT3, MMP9, IL2, FGF2, MAPK1, BCL2L1, MMP2, PTPN11, and MDM2, among which EGFR was the hub target. Western blotting results showed that EGFR protein level in myocardial tissue was significantly decreased after sepsis (P<0.05), whereas Rg5 treatment markedly upregulated its expression (P<0.05). Molecular docking predicted a strong interaction between Rg5 and EGFR, with a binding energy of -8.0 kcal/mol.

Ginsenoside Rg5 effectively ameliorates sepsis-induced myocardial contractile dysfunction, attenuates myocardial injury, and improves survival in septic mice. The underlying mechanism may be associated with its interaction with EGFR and upregulation of EGFR expression.