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<p>Heart failure with reduced ejection fraction (HFrEF) remains a major therapeutic challenge. B-cell lymphoma 2-associated transcription factor 1 (Bclaf1) is implicated in RNA splicing and cardiac disease, but its role in HFrEF pathogenesis is unknown. Here, we demonstrate that Bclaf1 expression is elevated in human HFrEF myocardium and in male murine pressure-overload models. Cardiac-specific Bclaf1 overexpression drives pathological hypertrophy and systolic dysfunction, whereas its genetic knockout or adeno-associated virus serotype 9 (AAV9)-mediated knockdown attenuates these phenotypes. Mechanistically, Bclaf1 interacts with the splicing factor serine/arginine-rich splicing factor 2 (Srsf2) to bind to heart and neural crest derivatives expressed 2 (Hand2) pre-mRNA and enhance its splicing efficiency, leading to increased mature Hand2 levels and maladaptive remodeling. Inhibition of either Bclaf1 or Hand2 rescues cardiac function and structure in experimental HFrEF. Our work defines a Bclaf1/Srsf2/Hand2 splicing axis as a critical driver of HFrEF and reveals a promising therapeutic target for heart failure.</p>

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Bclaf1 drives heart failure by recruiting Srsf2 to enhance Hand2 pre-mRNA splicing and pathological hypertrophy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月6日

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  • Yang Zhang,
  • Haiyu Gao,
  • Ying lu,
  • Yingzi Zhang,
  • Meng Yang,
  • Xiaofang Zhang,
  • Yinfeng Zhao,
  • Liying Yu,
  • Yinghe Zhai,
  • Shuang Wang,
  • Lexin Zhao,
  • Guohui Yang,
  • Jialiang Li,
  • Jiaxin Yu,
  • Chenhong Li,
  • Changzhu Li,
  • Yifan Wang,
  • Ying Yang,
  • Yue Li,
  • Luyang Yu,
  • Deli Zhao,
  • Lida Yang,
  • Lei Jiao,
  • Baofeng Yang,
  • Yanjie Lu,
  • Zhenwei Pan

摘要

Heart failure with reduced ejection fraction (HFrEF) remains a major therapeutic challenge. B-cell lymphoma 2-associated transcription factor 1 (Bclaf1) is implicated in RNA splicing and cardiac disease, but its role in HFrEF pathogenesis is unknown. Here, we demonstrate that Bclaf1 expression is elevated in human HFrEF myocardium and in male murine pressure-overload models. Cardiac-specific Bclaf1 overexpression drives pathological hypertrophy and systolic dysfunction, whereas its genetic knockout or adeno-associated virus serotype 9 (AAV9)-mediated knockdown attenuates these phenotypes. Mechanistically, Bclaf1 interacts with the splicing factor serine/arginine-rich splicing factor 2 (Srsf2) to bind to heart and neural crest derivatives expressed 2 (Hand2) pre-mRNA and enhance its splicing efficiency, leading to increased mature Hand2 levels and maladaptive remodeling. Inhibition of either Bclaf1 or Hand2 rescues cardiac function and structure in experimental HFrEF. Our work defines a Bclaf1/Srsf2/Hand2 splicing axis as a critical driver of HFrEF and reveals a promising therapeutic target for heart failure.