Reduced myocardial NRG-1/ErbB4 signaling is associated with STING-linked macrophage pyroptotic signaling in sepsis-induced cardiac injury

Sepsis-induced cardiac injury lacks a mechanism-specific therapy, and loss of endogenous myocardial defense signaling may amplify inflammatory damage. We investigated whether recombinant neuregulin-1 (rNRG-1) protects against cecal ligation and puncture (CLP)-induced cardiac injury and whether stimulator of interferon genes (STING)-linked macrophage pyroptosis-associated signaling contributes to this response. Male mice underwent CLP or sham surgery. Myocardial NRG-1/ErbB4 signaling was assessed over time, rNRG-1 was administered intravenously at 25 μg/kg immediately before CLP, and cardiac function, injury markers, inflammatory infiltration, survival, cGAS-STING signaling, and pyroptosis-associated readouts were evaluated. AAV-mediated STING overexpression was used to test whether STING activation weakens rNRG-1-mediated protection. CLP rapidly reduced myocardial NRG-1 abundance and ErbB4 phosphorylation, while NRG-1 and ErbB4 signals were detectable in vascular, myocardial, and CD68-positive inflammatory-cell-rich compartments. rNRG-1 improved left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), reduced serum creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), increased 14-day survival from 26.67% to 60.00%, and decreased myocardial CD68-positive macrophage accumulation and myeloperoxidase (MPO)-positive inflammatory cell infiltration. rNRG-1 also suppressed cGAS expression and the phosphorylation of STING, TBK1, IRF3, and NF-κB p65, while reducing NLRP3, cleaved caspase-1, GSDMD-N, and IL-18 levels, with fewer CD68-positive cells showing STING activation, downstream inflammatory signaling, or pyroptosis-associated markers. AAV-mediated STING overexpression worsened CLP-induced dysfunction and substantially weakened the functional, biochemical, inflammatory, and pyroptosis-associated signaling effects of rNRG-1. These findings indicate that polymicrobial sepsis is associated with reduced myocardial NRG-1/ErbB4 signaling and that rNRG-1 attenuates early septic cardiac injury in association with reduced STING-linked inflammatory and pyroptosis-associated signaling in CD68-positive, macrophage-rich myocardial regions, rather than establishing a macrophage-specific mechanism.