Protective role of IRG1/itaconate in acute myocardial injury: association with NLRP3 inflammasome and oxidative stress

Increasing evidence indicates the critical role of Immune response gene 1 (IRG1)-derived itaconate in metabolic regulation and signal transduction, with therapeutic implications for inflammatory diseases. However, its mechanistic involvement in acute myocardial injury remains unclear. This study investigated the protective effects of itaconate in LPS-induced acute myocardial injury. LPS exposure upregulated IRG1 expression and levels of itaconate in murine cardiac tissue, while IRG1 deficiency exacerbated myocardial inflammation (elevated BNP, CK-MB, TNF-α, IL-6, and MPO activity), cardiac dysfunction, and mortality. Mechanistically, IRG1 absence promoted NLRP3 inflammasome activation and oxidative stress. Administration of 4-octyl itaconate (4-OI), a cell-permeable itaconate derivative, mitigated LPS-induced acute myocardial injury, reduced pro-inflammatory cytokines, and improved cardiac function in both wild-type (WT) and IRG1 knockout (KO) mice. 4-OI also modulated oxidative stress and Nrf2 signaling. These findings demonstrate that IRG1/itaconate exerts protective effects in acute myocardial injury, and 4-OI may have the potential to prevent sepsis-related acute myocardial injury.