Macrophage-Specific SPP1 Contributes to Pressure Overload-Induced Cardiac Dysfunction and Maladaptive Remodeling.

Cardiac macrophages display remarkable functional plasticity via heterogeneous subpopulations and a dynamic secretome, orchestrating key regulatory events during pressure overload-induced myocardial remodeling. However, the specific pathogenic subsets and their core regulatory mechanisms remain insufficiently defined. In this study, we identified a pathogenic secreted phosphoprotein 1 (SPP1)-expressing macrophage subset that emerges early after transverse aortic constriction. Myeloid-specific deletion of Spp1 potently attenuated transverse aortic constriction-induced cardiac inflammation, pathological remodeling, and dysfunction. Mechanistically, stressed cardiomyocytes release high-mobility group box 1 (HMGB1), which triggers NLRP3 inflammasome activation in macrophages and subsequent SPP1 production via NF-κB p65. Targeting this HMGB1-NLRP3-SPP1 axis with arglabin, an emerging NLRP3 inhibitor, effectively suppressed myocardial SPP1 expression, restricted proinflammatory immune cell infiltration and cardiac fibrosis, and thereby alleviated adverse myocardial remodeling induced by pressure overload. Our findings delineate a critical HMGB1-NLRP3-NF-κB-SPP1 axis in macrophages that drives pressure overload-induced cardiac pathogenesis. Targeting this pathway, exemplified by the natural compound arglabin, represents a promising therapeutic strategy against pathological cardiac remodeling.