Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK

Chenxu Ge, Jun Tan (), Xianling Dai, Qin Kuang, Shaoyu Zhong, Lili Lai, Chao Yi, Yan Sun, Jing Luo, Chufeng Zhang (), Liancai Zhu (), Bochu Wang and Minxuan Xu ()
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Chenxu Ge: Chongqing University of Education
Jun Tan: Chongqing University of Education
Xianling Dai: Chongqing University of Education
Qin Kuang: Chongqing University of Education
Shaoyu Zhong: Chongqing University of Education
Lili Lai: Chongqing University of Education
Chao Yi: Chongqing University of Education
Yan Sun: Chongqing University of Education
Jing Luo: Chongqing University of Education
Chufeng Zhang: Shandong First Medical University & Shandong Academy of Medical Sciences
Liancai Zhu: Chongqing University
Bochu Wang: Chongqing University
Minxuan Xu: Chongqing University of Education

Nature Communications, 2022, vol. 13, issue 1, 1-21

Abstract: Abstract Nonalcoholic steatohepatitis (NASH), a common clinical disease, is becoming a leading cause of hepatocellular carcinoma (HCC). Dual specificity phosphatase 22 (DUSP22, also known as JKAP or JSP-1) expressed in numerous tissues plays essential biological functions in immune responses and tumor growth. However, the effects of DUSP22 on NASH still remain unknown. Here, we find a significant decrease of DUSP22 expression in human and murine fatty liver, which is mediated by reactive oxygen species (ROS) generation. Hepatic-specific DUSP22 deletion particularly exacerbates lipid deposition, inflammatory response and fibrosis in liver, facilitating NASH and non-alcoholic fatty liver disease (NAFLD)-associated HCC progression. In contrast, transgenic over-expression, lentivirus or adeno-associated virus (AAV)-mediated DUSP22 gene therapy substantially inhibit NASH-related phenotypes and HCC development in mice. We provide mechanistic evidence that DUSP22 directly interacts with focal adhesion kinase (FAK) and restrains its phosphorylation at Tyr397 (Y397) and Y576 + Y577 residues, subsequently prohibiting downstream activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) cascades. The binding of DUSP22 to FAK and the dephosphorylation of FAK are indispensable for DUSP22-meliorated NASH progression. Collectively, our findings identify DUSP22 as a key suppressor of NASH-HCC, and underscore the DUSP22-FAK axis as a promising therapeutic target for treatment of the disease.

Date: 2022
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DOI: 10.1038/s41467-022-33493-5

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