Abstract
<title>Abstract</title> <p>Rheumatic heart disease (RHD), triggered by Group A β-hemolytic Streptococcus, features valvular inflammation and fibrosis. The role of neutrophil extracellular traps (NETs) in RHD valvular injury remains unclarified. Here we established a rat RHD model and performed RNA sequencing on mitral valves to screen key NETs-related genes. RT-qPCR, Western blotting, immunohistochemistry and immunofluorescence were used for validation. RHD rats showed enhanced inflammatory infiltration, increased IL-6, IL-17 and severe valvular fibrosis. We identified 89 differentially expressed genes enriched in immune and inflammatory pathways, and nine upregulated hub NETs genes. S100A8 and S100A9 had the highest expression fold change, with their mRNA and protein levels markedly elevated alongside increased NETs markers MPO and citH3. This study confirms the S100A8/S100A9-NETs axis mediates RHD valvular damage: S100A8/S100A9 activates neutrophils to induce excessive NETs, driving inflammation, abnormal collagen deposition and valvular fibrotic remodeling.</p>