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<p>Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease. Available therapies show inconsistent results on fibrosis, probably due to heterogeneity in disease trajectory or incomplete understanding of molecular determinants. Here we identified increased <i>KCTD17</i> levels in patients with MASH, and in dietary rodent models of MASH—such as those fed a diet high in palmitate, sucrose and cholesterol coupled with fructose-containing drinking water or a choline-deficient, <span>l</span>-amino acid-defined, high-fat diet—which showed an inverse correlation with the expression of serine protease inhibitor a3k (<i>SERPINA3</i> in humans, <i>Serpina3k</i> in mice). KCTD17 depletion increased <i>SERPINA3</i> levels and reduced liver fibrosis in mice fed a MASH-inducing diet by inhibiting Par2/TGFβ-mediated activation of hepatic stellate cells. Mechanistically, Kctd17 regulates <i>Serpina3k</i> expression by facilitating the ubiquitin-mediated degradation of Zbtb7b, which in turn diminishes Serpina3k secretion. Consequently, pharmacological inhibition of Kctd17 effectively reverses MASH-induced liver fibrosis. In summary, these findings underscore the therapeutic potential of targeting KCTD17 for the treatment of MASH-induced liver fibrosis.</p>

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Hepatocyte KCTD17-mediated SERPINA3 inhibition determines liver fibrosis in metabolic dysfunction-associated steatohepatitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月1日

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  • Yelin Jeong,
  • Ah-Reum Oh,
  • Young Hoon Jung,
  • Kyung Hee Jung,
  • Seongju Lee,
  • Michele Carrer,
  • Sang Bae Lee,
  • Luca Valenti,
  • Utpal B. Pajvani,
  • KyeongJin Kim

摘要

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease. Available therapies show inconsistent results on fibrosis, probably due to heterogeneity in disease trajectory or incomplete understanding of molecular determinants. Here we identified increased KCTD17 levels in patients with MASH, and in dietary rodent models of MASH—such as those fed a diet high in palmitate, sucrose and cholesterol coupled with fructose-containing drinking water or a choline-deficient, l-amino acid-defined, high-fat diet—which showed an inverse correlation with the expression of serine protease inhibitor a3k (SERPINA3 in humans, Serpina3k in mice). KCTD17 depletion increased SERPINA3 levels and reduced liver fibrosis in mice fed a MASH-inducing diet by inhibiting Par2/TGFβ-mediated activation of hepatic stellate cells. Mechanistically, Kctd17 regulates Serpina3k expression by facilitating the ubiquitin-mediated degradation of Zbtb7b, which in turn diminishes Serpina3k secretion. Consequently, pharmacological inhibition of Kctd17 effectively reverses MASH-induced liver fibrosis. In summary, these findings underscore the therapeutic potential of targeting KCTD17 for the treatment of MASH-induced liver fibrosis.