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Hepatocyte KCTD17-mediated SERPINA3 inhibition determines liver fibrosis in metabolic dysfunction-associated steatohepatitis
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DOI：10.1038/s12276-025-01499-w.png)
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Abstract
En 中文
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. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects about 25% of people worldwide. Around 20% of these cases progress to a more severe form, leading to liver damage and potentially requiring a liver transplant. Researchers studied a protein called KCTD17, which is involved in liver fibrosis. They found that reducing KCTD17 in mice with MASLD decreased liver damage. The study used mice fed a special diet to mimic human liver disease. The researchers used genetic techniques to lower KCTD17 levels and observed less liver scarring. They also discovered that KCTD17 affects another protein, Serpina3k, which helps protect the liver. Increasing Serpina3k levels reduced liver damage in mice. These findings suggest that targeting KCTD17 could be a new way to treat liver fibrosis. In the future, it could lead to new treatments for people with severe liver disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
Keywords:
KCTD17
SERPINA3
liver fibrosis
metabolic dysfunction-associated steatohepatitis
hepatic stellate cells
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