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<p>Septic cardiomyopathy (SCM) exhibits over 70% mortality, primarily attributed to cardiomyocyte metabolic reprogramming shifting from oxidative phosphorylation (OXPHOS) to glycolysis. Although transforming growth factor-β3(TGF-β3) modulates energy metabolism in other tissues, its function in SCM pathogenesis remains unexplored.&#xa0;In vivo, cecal ligation puncture (CLP) rat models received myocardial injections of TGF-β3-overexpressing or interfering adenovirus. Myocardial injury through histopathology (H&amp;E) and apoptosis (TUNEL), and mitochondrial ultrastructure via transmission electron microscopy (TEM). In vitro, primary cardiomyocytes treated with lipopolysaccharide (LPS) were transfected with TGF-β3 overexpression plasmid, with metabolic analyzed using Seahorse XF technology (extracellular acidification rate, ECAR; oxygen consumption rate, OCR). Molecular mechanisms were investigated via Western blotting and co-immunoprecipitation (Co-IP) targeting TGF-β3/Smad7/SKP1 signaling.&#xa0;TGF-β3 was significantly downregulated in SCM. Its overexpression attenuated myocardial injury and apoptosis, improved mitochondrial integrity, and reversed metabolic reprogramming by reducing glycolysis while enhancing OXPHOS. Mechanistically, TGF-β3 promoted Smad7 phosphorylation to inhibit Smad2/3 activation and suppressed SKP1 expression to reduce Smad7 ubiquitination, as confirmed by Co-IP.&#xa0;TGF-β3 confers cardioprotection in SCM by reversing metabolic reprogramming through dual regulation of Smad7: enhancing phosphorylation to block Smad2/3 signaling and inhibiting SKP1-mediated ubiquitination to stabilize Smad7. This newly identified TGF-β3/Smad7 axis represents a promising therapeutic target for SCM.</p>

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Transforming growth factor-β3 attenuates septic cardiomyopathy by reversing cardiomyocyte metabolic reprogramming through Smad7 signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月2日

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  • Hongxuan Zhang,
  • Jingqing Xu,
  • Bing Xu,
  • Xiuling Shang

摘要

Septic cardiomyopathy (SCM) exhibits over 70% mortality, primarily attributed to cardiomyocyte metabolic reprogramming shifting from oxidative phosphorylation (OXPHOS) to glycolysis. Although transforming growth factor-β3(TGF-β3) modulates energy metabolism in other tissues, its function in SCM pathogenesis remains unexplored. In vivo, cecal ligation puncture (CLP) rat models received myocardial injections of TGF-β3-overexpressing or interfering adenovirus. Myocardial injury through histopathology (H&E) and apoptosis (TUNEL), and mitochondrial ultrastructure via transmission electron microscopy (TEM). In vitro, primary cardiomyocytes treated with lipopolysaccharide (LPS) were transfected with TGF-β3 overexpression plasmid, with metabolic analyzed using Seahorse XF technology (extracellular acidification rate, ECAR; oxygen consumption rate, OCR). Molecular mechanisms were investigated via Western blotting and co-immunoprecipitation (Co-IP) targeting TGF-β3/Smad7/SKP1 signaling. TGF-β3 was significantly downregulated in SCM. Its overexpression attenuated myocardial injury and apoptosis, improved mitochondrial integrity, and reversed metabolic reprogramming by reducing glycolysis while enhancing OXPHOS. Mechanistically, TGF-β3 promoted Smad7 phosphorylation to inhibit Smad2/3 activation and suppressed SKP1 expression to reduce Smad7 ubiquitination, as confirmed by Co-IP. TGF-β3 confers cardioprotection in SCM by reversing metabolic reprogramming through dual regulation of Smad7: enhancing phosphorylation to block Smad2/3 signaling and inhibiting SKP1-mediated ubiquitination to stabilize Smad7. This newly identified TGF-β3/Smad7 axis represents a promising therapeutic target for SCM.