Cardiomyopathy accounts for worse clinical outcome and higher mortality rate during sepsis globally. Here we assessed whether post-operative administration of I-C-F-6, a small molecule oligo-peptide (Gly-Ala-Gly-Pro-His-Gly-Gly) derived from Carapax trionycis, protected against septic cardiomyopathy in mice. Male adult mice were exposed to cecal ligation and puncture (CLP) and I-C-F-6 was administered intravenously (0.4 mg/kg or 4.0 mg/kg) 30 min following surgery. Administration of I-C-F-6 extended survival period and decreased sepsis severity score in septic mice. Furthermore, administration of I-C-F-6 mitigated cardiac atrophy and preserved cardiac function in septic mice. Mechanistically, I-C-F-6 inhibited inflammation and promoted M2 polarization in myocardium of septic mice. In addition, I-C-F-6 activated nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4) pathway, mitigated oxidative damage and inhibited ferroptosis in myocardium of septic mice. In conclusion, post-operative administration of I-C-F-6 in mice exposed to CLP improved survival and mitigated myocardial impairment. Our work established a clear therapeutic potential of I-C-F-6 for sepsis-induced cardiomyopathy.
