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<p>Non-alcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), have emerged as a burgeoning global epidemic and impose an enormous socioeconomic burden. However, the lack of effective pharmacotherapies is due to incomplete understanding of the molecular mechanisms of NASH. In the present study, we observe that E3 ligase TRIM7 expression is significantly increased in both liver tissues and hepatocytes from NAFLD models. In vivo gain- and loss-of-function experiments reveal that hepatic-specific TRIM7 deletion significantly alleviates hepatic steatosis, inflammation and insulin resistance in diet-induced male mouse models, whereas overexpression of wild-type TRIM7 (but not its E3-deficient mutant) shows diametrically opposite effects. Mechanistic studies reveal that TRIM7 interacts with and catalyzes DUSP10 ubiquitination and proteasomal degradation, thus leading to hyperactivation of IKKβ-NF-κB and JNK/p38 MAPK signaling pathways. Importantly, silencing DUSP10 expression abrogates the protective effects of hepatic TRIM7 deficiency on NAFLD-related pathological phenotypes. Collectively, our findings identify TRIM7 as a key regulator of the pathogenesis of NAFLD/NASH and provide a promising therapeutic strategy for NAFLD by targeting the TRIM7-DUSP10 axis.</p>

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The E3 ligase tripartite motif 7 drives the progression of non-alcoholic fatty liver disease by targeting DUSP10 degradation in male mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Feng-Juan Yan,
  • Han Ding,
  • Ning Zhang,
  • Shi-Ran Yan,
  • Mei-Xin Huang,
  • Jing-Wei Lu,
  • Yong-Jian Wang,
  • Yu-Jie Yan,
  • Rong-Peng Li,
  • Qun Wang

摘要

Non-alcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), have emerged as a burgeoning global epidemic and impose an enormous socioeconomic burden. However, the lack of effective pharmacotherapies is due to incomplete understanding of the molecular mechanisms of NASH. In the present study, we observe that E3 ligase TRIM7 expression is significantly increased in both liver tissues and hepatocytes from NAFLD models. In vivo gain- and loss-of-function experiments reveal that hepatic-specific TRIM7 deletion significantly alleviates hepatic steatosis, inflammation and insulin resistance in diet-induced male mouse models, whereas overexpression of wild-type TRIM7 (but not its E3-deficient mutant) shows diametrically opposite effects. Mechanistic studies reveal that TRIM7 interacts with and catalyzes DUSP10 ubiquitination and proteasomal degradation, thus leading to hyperactivation of IKKβ-NF-κB and JNK/p38 MAPK signaling pathways. Importantly, silencing DUSP10 expression abrogates the protective effects of hepatic TRIM7 deficiency on NAFLD-related pathological phenotypes. Collectively, our findings identify TRIM7 as a key regulator of the pathogenesis of NAFLD/NASH and provide a promising therapeutic strategy for NAFLD by targeting the TRIM7-DUSP10 axis.