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<p>Reduced expression and activity of cardiac sarco/endoplasmic reticulum Ca<sup>2+</sup>-ATPase 2a (SERCA2a), causing intracellular calcium dyshomeostasis, are regarded as hallmarks of heart failure (HF). However, effective SERCA2a-targeted therapies for HF treatment have not been identified. Here, we show that fluorofenidone, previously reported to enhance cell shortening, contraction and relaxation of cardiomyocytes by nearly 100%, prevents the progression of pressure overload-induced HF. Combining drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) approaches, we identify SERCA2a as a direct binding partner of fluorofenidone. Mechanistically, fluorofenidone attenuates the binding of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) to SERCA2a and inhibits WWP1-mediated K27-linked polyubiquitination of SERCA2a. Moreover, Gln758, Asp812 and Glu917 are essential for the fluorofenidone-SERCA2a interaction. SERCA2a knockdown markedly attenuated the cardioprotective effects of fluorofenidone on pressure overload-induced HF in male mice. Together, these findings highlight the therapeutic potential of fluorofenidone for HF treatment. Nevertheless, further preclinical and clinical studies are required to fully evaluate its in vivo efficacy and safety before clinical translation.</p>

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Fluorofenidone ameliorates pressure overload-induced heart failure by stabilizing SERCA2a in male mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Quan Liu,
  • Huayang Li,
  • Jiantao Chen,
  • Qiushi Ren,
  • Tongxin Chu,
  • Li Luo,
  • Zeyu Li,
  • Suiqing Huang,
  • Liqun Shang,
  • Adilai Maihemuti,
  • Zhuoming Zhou,
  • Zhilin Miao,
  • Kaizheng Liu,
  • Jinyu Pan,
  • Kangni Feng,
  • Mengya Liang,
  • Zhongkai Wu

摘要

Reduced expression and activity of cardiac sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a), causing intracellular calcium dyshomeostasis, are regarded as hallmarks of heart failure (HF). However, effective SERCA2a-targeted therapies for HF treatment have not been identified. Here, we show that fluorofenidone, previously reported to enhance cell shortening, contraction and relaxation of cardiomyocytes by nearly 100%, prevents the progression of pressure overload-induced HF. Combining drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) approaches, we identify SERCA2a as a direct binding partner of fluorofenidone. Mechanistically, fluorofenidone attenuates the binding of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) to SERCA2a and inhibits WWP1-mediated K27-linked polyubiquitination of SERCA2a. Moreover, Gln758, Asp812 and Glu917 are essential for the fluorofenidone-SERCA2a interaction. SERCA2a knockdown markedly attenuated the cardioprotective effects of fluorofenidone on pressure overload-induced HF in male mice. Together, these findings highlight the therapeutic potential of fluorofenidone for HF treatment. Nevertheless, further preclinical and clinical studies are required to fully evaluate its in vivo efficacy and safety before clinical translation.