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<p>In hypertrophic and failing hearts, fuel metabolism is reprogrammed toward enhanced glycolysis. Here, we identify asprosin, an adipokine, as a critical regulator of this process in pathological cardiac hypertrophy. In patients, circulating asprosin levels correlate with NT-proBNP and EF. Cardiomyocyte-specific asprosin overexpression aggravates hypertrophy, abnormal glycolysis, and impairs mitochondrial ATP production in male mice, whereas its deficiency confers protection against TAC- or Ang II-induced remodeling in male/female mice. Mechanistically, asprosin binds PFKP and inhibits the K48-linked ubiquitination by DTX3L, thereby stabilizing PFKP and driving aberrant glycolysis, PDK4 induction, PDH inhibition, and impaired respiration. Genetic knockdown of PFKP mitigates hypertrophy and fibrosis in male mice, whereas PFKP overexpression abolishes the protective effects conferred by FBN1 knockdown. Moreover, YY1 is identified as a transcriptional activator of asprosin in the hypertrophic hearts of male mice. Here we show that the YY1–asprosin–PFKP–PDK4–PDH axis underlies metabolic remodeling, and we highlight plasma asprosin as a potential early biomarker and therapeutic target for cardiac dysfunction.</p>

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YY1/Asprosin/PFKP axis regulates glycolytic metabolic and exacerbates pathological cardiac hypertrophy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • Ming Tong,
  • Xinxin Liu,
  • Yuanyuan Yu,
  • Yue Zhang,
  • Jiangfei Zheng,
  • Yanxi Li,
  • Huan Chen,
  • Linhe Liu,
  • Yanrong Li,
  • Zhengkai Wang,
  • Yi Chen,
  • Shifeng Cao,
  • Qi Zhang,
  • Honglin Jia,
  • Shuyu Liu,
  • Houwei Li,
  • Xue Liu,
  • Yixiu Zhao,
  • Zhimin Du,
  • Yan Zhang

摘要

In hypertrophic and failing hearts, fuel metabolism is reprogrammed toward enhanced glycolysis. Here, we identify asprosin, an adipokine, as a critical regulator of this process in pathological cardiac hypertrophy. In patients, circulating asprosin levels correlate with NT-proBNP and EF. Cardiomyocyte-specific asprosin overexpression aggravates hypertrophy, abnormal glycolysis, and impairs mitochondrial ATP production in male mice, whereas its deficiency confers protection against TAC- or Ang II-induced remodeling in male/female mice. Mechanistically, asprosin binds PFKP and inhibits the K48-linked ubiquitination by DTX3L, thereby stabilizing PFKP and driving aberrant glycolysis, PDK4 induction, PDH inhibition, and impaired respiration. Genetic knockdown of PFKP mitigates hypertrophy and fibrosis in male mice, whereas PFKP overexpression abolishes the protective effects conferred by FBN1 knockdown. Moreover, YY1 is identified as a transcriptional activator of asprosin in the hypertrophic hearts of male mice. Here we show that the YY1–asprosin–PFKP–PDK4–PDH axis underlies metabolic remodeling, and we highlight plasma asprosin as a potential early biomarker and therapeutic target for cardiac dysfunction.