Role of SIRT1-HMGB1-NLRP3 inflammasome axis in the protective effects of trans-chalcone on myocardial ischemia and reperfusion injury.

Myocardial ischemia and reperfusion (MIR) injury, a major cause of cardiovascular morbidity, involves oxidative stress, inflammation, and cell death. This study examines the protective effects of trans-chalcone, a natural flavonoid, on MIR-induced myocardial damage via the Sirtuin 1 (SIRT1)-High Mobility Group Box 1 (HMGB1)-inflammasome-pyroptosis axis. Young adult male Sprague-Dawley rats were subjected to MIR injury and treated with trans-chalcone (100 mg/kg) or the SIRT1 inhibitor EX-527 intraperitoneally for seven days prior to MIR induction. Cardiac function, infarct size, mitochondrial function, oxidative stress, inflammasome and pyroptosis markers were assessed, alongside protein expression analysis of SIRT1, HMGB1, caspase-1, gasdermin D N-terminal fragment, Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), and Nuclear Factor Kappa B-subunit 65 (NF-κB-p65). Trans-chalcone treatment significantly improved left ventricular pressures, infarct size, and mitochondrial function compared to untreated MIR rats. Oxidative stress was reduced, as shown by decreased malondialdehyde and increased glutathione levels. Western blot analysis confirmed upregulation of SIRT1 and Nrf2 and downregulation of HMGB1, NOD-like receptor protein 3 (NLRP3), cleaved-caspase-1, gasdermin D, and NF-κB-p65. SIRT1 inhibition by EX-527 diminished these protective effects, emphasizing SIRT1's role in trans-chalcone-mediated cardioprotection. These results indicate that trans-chalcone mitigates myocardial MIR injury by targeting SIRT1 to suppress HMGB1, enhance mitochondrial function, and reduce oxidative stress, inflammasome, and pyroptotic markers, positioning trans-chalcone as a promising therapeutic option for ischemic heart disease.