Axin formation inhibitor 1 aggravates hepatic ischemia‒reperfusion injury by promoting the ubiquitination and degradation of PPARβ

Baolin Qian, Bing Yin, Hongjun Yu, Chaoqun Wang, Shounan Lu, Shanjia Ke, Zihao Li, Xinglong Li, Yongliang Hua, Zhongyu Li, Yongzhi Zhou, Zhanzhi Meng, Yao Fu, Wei Tang and Yong Ma ()
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Baolin Qian: The First Affiliated Hospital of Harbin Medical University
Bing Yin: The First Affiliated Hospital of Harbin Medical University
Hongjun Yu: The First Affiliated Hospital of Harbin Medical University
Chaoqun Wang: The First Affiliated Hospital of Harbin Medical University
Shounan Lu: The First Affiliated Hospital of Harbin Medical University
Shanjia Ke: The First Affiliated Hospital of Harbin Medical University
Zihao Li: The First Affiliated Hospital of Harbin Medical University
Xinglong Li: The First Affiliated Hospital of Harbin Medical University
Yongliang Hua: The First Affiliated Hospital of Harbin Medical University
Zhongyu Li: The First Affiliated Hospital of Harbin Medical University
Yongzhi Zhou: The First Affiliated Hospital of Harbin Medical University
Zhanzhi Meng: The First Affiliated Hospital of Harbin Medical University
Yao Fu: The First Affiliated Hospital of Harbin Medical University
Wei Tang: National Center for Global Health and Medicine
Yong Ma: The First Affiliated Hospital of Harbin Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Hepatic ischemia‒reperfusion injury (HIRI) is a common pathological phenomenon after hepatectomy and liver transplantation. Here, we aim to explore the role of Axin formation inhibitor 1 (Axin1) in HIRI. In this work, we find that the expression of Axin1 is upregulated after HIRI. Cellular experiments confirme that Axin1 knockdown alleviated hypoxia/reoxygenation (H/R)-induced inflammation and apoptosis. Subsequently, we construct a HIRI model based on transgenic hepatocellular-specific Axin1 knockout and overexpression male mice and find that Axin1 deletion alleviated inflammation and apoptosis. Transcriptome sequencing reveal that the genes whose expression differed after Axin1 overexpression are significantly enriched in the PPAR signaling pathway. Furthermore, we demonstrate that Axin1 negatively regulates the expression of PPARβ, thereby activating the NF-κB pathway. Mechanistically, Axin1 binds to PPARβ to enhance the ubiquitination-mediated degradation of PPARβ by the E3 ubiquitin ligase RBBP6. Notably, adenovirus-mediated Axin1 knockdown block I/R damage in mice. Our study results demonstrate that Axin1 exacerbates HIRI by promoting the ubiquitination and degradation of PPARβ, which in turn activates the NF-κB signaling pathway. These results suggest that Axin1 may be a potential therapeutic target for HIRI.

Date: 2025
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DOI: 10.1038/s41467-025-56967-8

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