Dapansutrile alleviates sepsis-induced cardiac injury by modulating NF-кB-induced inflammatory response and TXNIP/NLRP3/ GSDMD-mediated pyroptosis

Sepsis-induced multi-organ toxicities are severe complications characterized by multiple organ failure, including the heart, and are associated with high mortality. Recently, a novel NLRP3 inhibitor, dapansutrile (DAPA), has shown potent anti-inflammatory and antioxidant properties. However, its effect on septic cardiac injury remains unknown. This study investigated the efficacy of DAPA in safeguarding against lipopolysaccharide (LPS)-induced cardiac injury and explored its underlying mechanisms. DAPA pretreatment successfully protected mice from septic cardiac injury. DAPA attenuated the biochemical indices of cardiotoxicity and pathological cardiac lesions caused by LPS. DAPA also boosted endogenous antioxidants (TAC, GSH, CAT, and SOD) in the cardiac tissue. Simultaneously, the oxidative burden of the cardiac tissue was decreased, as revealed by a decrease in the indicators of lipid peroxidation (8-OHdG, PC, MDA, and 4-HNE). The oxidative-driven inflammation induced by LPS was greatly suppressed by DAPA, as shown by the remarkable decrease in the gene expression and levels of inflammatory cytokines in the cardiac tissue. DAPA counteracted NF-κB activation. Concurrently, DAPA inhibited the TXNIP/NLRP3 axis and suppressed the activation of caspase-1 and IL-1β. This was evident in the results of their genetic and protein analyses of caspase-1/IL-1β. Additionally, DPAP ameliorated the increase in the pyroptotic marker, N-terminal domain of gasdermin D (GSDMD-N), induced by LPS injection. Collectively, our findings suggest that DAPA exerts cardioprotective effects by inhibiting the NF-κB/cytokine and TXNIP/NLRP3/caspase-1/IL-1β/GSDMD-N signalling pathways, positioning it as a potential therapeutic candidate for septic cardiac injury.