Interferon regulatory factor 1 promotes pyroptosis and inflammation in mouse sepsis-induced cardiomyopathy

Although pyroptosis is involved in sepsis and sepsis-induced cardiomyopathy (SIC), the underlying mechanism remains unclear. This study aimed to investigate the role and mechanims of myocardial pyroptosis in the progression of SIC. We first identified differentially expressed genes and hub pyroptosis-related genes (PRGs) in SIC using bioinformatics analyses and then constructed in vitro and in vivo SIC models to reveal the specific mechanisms of hub PRGs in SIC development. In this study, we confirmed eight hub PRGs (caspase-1, IRF1, IL-6, GSDMD, caspase-6, IL-1β, caspase-8, and ZBP1) as potential candidate biomarkers for SIC and their expression change in cardiac tissue and myocardial cells in sepsis was fully validated through a serials of in vivo and in vitro experiments. Additionally, KEGG analysis displayed that these hub PRGs were enriched for NOD-like receptor (NLR) signaling pathways and IRF1 is an upstream regulator of the NLRP3 inflammasome. SIC mice treated with IRF1 inhibitor, N-acetyl- l-cysteine (NAC), showed notable amelioration of cardiac histological injury, reduced levels of myocardial injury markers, and decreased expression of NLRP3, pyroptosis-related markers, and pro-inflammatory factors. The IRF1-knockdown H9C2 cells also exhibited markedly reduced expression of pro-inflammatory factors and pyroptosis-related markers. Overall, these findings suggest that IRF1 deficiency attenuates sepsis-induced myocardial injury by inhibiting pyroptosis and inflammation. Therefore, targeting IRF1 in cardiomyocytes may be a promising therapeutic strategy for preventing SIC.