Mechanism of total ginsenosides in alleviating myocardial injury in septic rat models by regulating SLC7A11/GPX4-mediated ferroptosis

Objective  To investigate the mechanism of total ginsenosides(TG) in alleviating myocardial injury in septic rat models by regulating solute carrier family 7 member 11/glutathione peroxidase 4 (SLC7A11/GPX4)-mediated ferroptosis.

Methods  Ninety SPF-grade male rats were randomly divided into five groups: Sham group(sham operation), septic cardiomyopathy (SCM) group, TG40 group (SCM model rats gavaged with 40 mg/kg TG), TG160 group (SCM model rats gavaged with 160 mg/kg TG), and TG160+RSL3 group (SCM model rats gavaged with 160 mg/kg TG and intraperitoneally injected with 10 mg/kg ferroptosis inducer RSL3). The SCM model was established using the cecal ligation and puncture method. Cardiac function was assessed in each group. Hematoxylin-eosin (HE) staining was performed to observe pathological changes in myocardial tissue. Levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, creatine kinase-MB (CK-MB), myoglobin (Mb), and cardiac troponin I (cTnI) were measured by enzyme-linked immunosorbent assay. Protein expression levels of NADPH oxidase (NOX)1, NOX2, NOX4, SLC7A11, and GPX4 were detected by western blotting. Levels of Fe²⁺ and total iron in myocardial tissue were also determined.

Results  Compared with the Sham group, the SCM group exhibited decreased left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and protein expression of SLC7A11 and GPX4, along with increased levels of CK-MB, Mb, cTnI, TNF-α, IL-1β, IL-6, Fe²⁺, total iron, and protein expression of NOX1, NOX2, and NOX4 (P < 0.05). Compared with the SCM group, the TG40 and TG160 groups showed dose-dependent increases in LVEF, LVFS, and SLC7A11/GPX4 expression, as well as reductions in CK-MB, Mb, cTnI, TNF-α, IL-1β, IL-6, Fe, total iron, and NOX1/NOX2/NOX4 expression (P < 0.05). In contrast, the TG160+RSL3 group displayed lower LVEF, LVFS, and SLC7A11/GPX4 expression, and higher levels of the aforementioned biomarkers compared with the TG160 group (P < 0.05).

Conclusion  TG significantly suppresses sepsis-induced myocardial inflammation and oxidative stress, improves cardiac function, and mitigates myocardial injury, likely by inhibiting ferroptosis via activation of the SLC7A11/GPX4 signaling pathway.