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Background <p>Atrial fibrillation (AF) is a common arrhythmia often linked to myocardial fibrosis. This study investigates the molecular mechanisms underlying AF, focusing on <i>HSPA9</i> as a key regulator of fibrosis and its interaction with the TGF-β1/Smad pathway.</p> Methods <p>The GSE79768 dataset was employed for differential gene expression analysis. Weighted Gene Co-expression Network Analysis (WGCNA) identified key modules associated with AF. Functional enrichment analyses and Protein-Protein Interaction (PPI) networks were performed. Mouse cardiac fibroblasts were subjected to Angiotensin II (Ang II), and gene, protein, and functional analyses were conducted using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot (WB), immunofluorescence, Co-immunoprecipitation (Co-IP), Cell Counting Kit-8 (CCK-8), and cell migration assays. In vivo, Ang II-induced mice were detected with immunohistochemistry (IHC) and Hematoxylin and Eosin (H&amp;E) staining for fibrosis.</p> Results <p>WGCNA identified a strong correlation with the brown module, highlighting <i>HSPA9</i> as a key gene in AF. <i>HSPA9</i> was upregulated in AF tissues and Ang II-treated fibroblasts. Knockdown of <i>HSPA9</i> suppressed fibroblast proliferation, migration, and fibrosis marker expression. <i>HSPA9</i> interacts with <i>HMGB1</i> to stabilize it, activating the TGF-β1/Smad pathway. <i>HMGB1</i> overexpression reversed the effects of <i>HSPA9</i> knockdown. In vivo, <i>HSPA9</i> knockdown alleviated myocardial fibrosis. <i>HSPA9</i> inhibits autophagy via the TGF-β1/Smad pathway, making it a possible target for treatment for AF and fibrosis.</p> Conclusion <p><i>HSPA9</i> regulates myocardial fibrosis in AF by interacting with <i>HMGB1</i> and activating the TGF-β1/Smad pathway. Targeting <i>HSPA9</i> could be a promising therapeutic strategy for preventing or treating AF-associated myocardial fibrosis.</p>

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HSPA9/HMGB1 regulates myocardial fibrosis in atrial fibrillation via TGF-β1/Smad pathway and autophagy

  • 期刊论文

  • 发表日期：

    2025年8月11日

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  • Fei Pan,
  • Jiaqi Gan,
  • Mengting Hu,
  • Yi Song,
  • Xiao Wu

摘要

Background

Atrial fibrillation (AF) is a common arrhythmia often linked to myocardial fibrosis. This study investigates the molecular mechanisms underlying AF, focusing on HSPA9 as a key regulator of fibrosis and its interaction with the TGF-β1/Smad pathway.

Methods

The GSE79768 dataset was employed for differential gene expression analysis. Weighted Gene Co-expression Network Analysis (WGCNA) identified key modules associated with AF. Functional enrichment analyses and Protein-Protein Interaction (PPI) networks were performed. Mouse cardiac fibroblasts were subjected to Angiotensin II (Ang II), and gene, protein, and functional analyses were conducted using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot (WB), immunofluorescence, Co-immunoprecipitation (Co-IP), Cell Counting Kit-8 (CCK-8), and cell migration assays. In vivo, Ang II-induced mice were detected with immunohistochemistry (IHC) and Hematoxylin and Eosin (H&E) staining for fibrosis.

Results

WGCNA identified a strong correlation with the brown module, highlighting HSPA9 as a key gene in AF. HSPA9 was upregulated in AF tissues and Ang II-treated fibroblasts. Knockdown of HSPA9 suppressed fibroblast proliferation, migration, and fibrosis marker expression. HSPA9 interacts with HMGB1 to stabilize it, activating the TGF-β1/Smad pathway. HMGB1 overexpression reversed the effects of HSPA9 knockdown. In vivo, HSPA9 knockdown alleviated myocardial fibrosis. HSPA9 inhibits autophagy via the TGF-β1/Smad pathway, making it a possible target for treatment for AF and fibrosis.

Conclusion

HSPA9 regulates myocardial fibrosis in AF by interacting with HMGB1 and activating the TGF-β1/Smad pathway. Targeting HSPA9 could be a promising therapeutic strategy for preventing or treating AF-associated myocardial fibrosis.