Spermidine diminishes lipopolysaccharide-induced myocardial ferroptosis through the Keap1-Nrf2/HO-1 pathway

Spermidine (SPD) is a naturally-occurring polyamine with a range of unique properties including anti-inflammatory, antioxidant, and cardioprotective effects. Ferroptosis, a form of cell death that is regulated by reactive oxygen species (ROS), plays a pivotal role in sepsis-induced cardiomyopathy. However, the interplay among spermidine levels, septic myocardial injury, and ferroptosis is unclear. This study aimed to investigate the effect of spermidine on ferroptosis and the underlying mechanisms of lipopolysaccharide (LPS)-induced acute myocardial damage during sepsis. A septic myocardial injury model was established using LPS treatment of H9c2 cells and C57BL/6 mice. Spermidine mitigated LPS-induced myocardial injury, decreased inflammatory responses and oxidative stress, and inhibited cardiomyocyte ferroptosis in both cellular and animal models. Spermidine reduced intracellular iron and malondialdehyde levels, while elevating glutathione levels and the expression of cardiac ferroptosis-related proteins. SPD was found to suppress lipid peroxidation and ferroptosis by activating the expression of nuclear factor erythroid 2-related factor 2 (Nrf2). Silencing Nrf2 ceased the inhibitory effect of SPD on ferroptosis in H9c2 cells. Spermidine exerted a protective effect against LPS-induced acute myocardial injury and may ameliorate LPS-induced septic myocardial ferroptosis via the Nrf2 pathway.