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

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 () and Qun Wang ()
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Feng-Juan Yan: Jiangsu Normal University, School of Life Science
Han Ding: Jiangsu Normal University, School of Life Science
Ning Zhang: Jiangsu Normal University, School of Life Science
Shi-Ran Yan: Heze Municipal Hospital Affiliated to Shandong First Medical University, Department of Cardiology
Mei-Xin Huang: Jiangsu Normal University, School of Life Science
Jing-Wei Lu: Jiangsu Normal University, School of Life Science
Yong-Jian Wang: Jiangsu Normal University, School of Life Science
Yu-Jie Yan: Jiangsu Normal University, School of Life Science
Rong-Peng Li: Jiangsu Normal University, School of Life Science
Qun Wang: Huazhong University of Science and Technology, Department of Hepatopancreatobiliary Surgery, Hubei Cancer Hospital, Tongji Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65415-6

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