Abstract Body (Do not enter title and authors here): Introduction:Hypertrophic Cardiomyopathy (HCM) is an inherited heart disease and the pathogenesis of HCM involves genetic mutations, hemodynamic stress, and metabolic factors, with myocardial fibrosis playing a crucial role in severe clinical events. IL-33/ST2 signaling pathway known for its roles in immune response and tissue repair, participates in cardiac protection and anti-cardiac fibrosis in heart failure. The role of ST2 in HCM remains unclear, and IL-33/ST2 pathway and broader inflammatory responses may be critical in HCM.

Hypothesis:ST2 gene downregulation and dysregulation of inflammatory pathways represent a novel mechanism in HCM.

Methods:We re-analyzed the raw whole transcriptome sequencing data using a comprehensive bioinformatics pipeline from 9 GEO datasets. After removing low-quality samples, myocardial tissue samples from 109 HCM patients and 210 non-HCM controls were included. HTSeq-count was used to obtain the read count of each gene. Differential expression analyses were conducted using DESeq2. Spearman correlation analysis was performed for ST2 with all other protein-coding genes. Gene set enrichment analysis (GSEA) was performed to explore the biological significance of ST2 related genes. CIBERSORTx was used to estimate the immune cell composition of heart tissues. Additionally, network analyses and statistical correlations were conducted.

Results:Our analysis identified significant downregulation of the ST2 gene in HCM patients compared to controls (log2FC = -5.0, p = 2.7E-147). In total, 5,180 upregulated and 741 downregulated genes were detected. Additionally, 208 genes were significantly correlated with the expression of ST2. GSEA based on the correlation coefficients revealed a significant increase in immune response, inflammation, and IFN-γ pathway activity, along with a decrease in the expression of genes related to sarcomeric function, cardiac morphogenesis, and metabolism in HCM. Notably, the significant inverse correlation between ST2 expression and regulatory T cells (r = -0.34) and a positive correlation with neutrophils (r = 0.39) suggest that ST2 may modulate immune cell populations in HCM. Pathway analysis indicated ST2's central role in networks involving inflammatory and fibrotic responses.

Conclusion:The interplay between ST2 and inflammatory pathways may drive myocardial remodeling and fibrosis in HCM. This study paves a new way for investigating pathogenic mechanisms and therapeutic strategies for HCM.