On October 8, 2022, the Chongqing University team and Shandong First Medical University and other teams published a research paper entitled "Hepatocyte Phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK" in Nature Communications.

This article is original by Translational Medicine Network. Please indicate the source when reprinting

Author: Mia

Introduction: Non-alcoholic steatohepatitis (NASH) is a common clinical disease and is becoming the main cause of hepatocellular carcinoma (HCC). Bispecific phosphatase 22 (DUSP22, also known as JKAP or JSP-1), expressed in numerous tissues, plays an important biological role in immune response and tumor growth. However, the effect of DUSP22 on NASH remains unknown.

On October 8, 2022, the Chongqing University team and Shandong First Medical University and other teams published a research paper entitled "Hepatocyte Phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK" on Nature Communications. This study identified DUSP22 as a key inhibitor of the development of NASH into an HCC process and emphasized that the DUSP22-FAK axis is a promising therapeutic target for the disease.

https://www.nature.com/articles/s41467-022-33493-5

Research background

01

Non-alcoholic steatohepatitis (NASH) usually occurs after non-alcoholic fatty liver disease (NAFLD) with simple hepatic steatosis, affecting about 40% of adults, and its prevalence has increased sharply in recent decades. NASH is becoming the main pathogenic promoter of end-stage liver diseases such as HCC and liver failure. The pathogenesis of NASH is characterized by hepatic steatosis, hepatocyte swelling, lobular inflammation and fibrosis. In addition, NASH is often accompanied by metabolic abnormalities, including hyperglycemia , obesity and type 2 diabetes (T2D). However, due to incomplete understanding of the pathogenesis of NASH, no approved effective drug therapy is available.

Some molecular events are activated under metabolic stress, resulting in liver steatosis. For example, nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signals, they play multiple functions in cell survival and death, glycolipid metabolism, and meta-inflammatory. Bispecific phosphatases (DUSPs), including MAPK phosphatases, mediate the activation of various downstream kinases through serine , threonine or tyrosine dephosphorylation. DUSP22 can regulate MAPK signaling and is expressed in various types of tissues and cells, suggesting that DUSP22 can regulate several key biological events such as inflammatory responses and tumor cell proliferation.

However, more and more recent studies have also been reported that DUSP22 also regulates many substrates in other signal cascades. Due to the widespread impact of DUSP22 on MAPKs activation, inflammation, and fibrosis-related diseases or responses, the researchers hypothesized that DUSP22 may have potential functional involvement in NASH pathogenesis and related HCC.

Study Overview

02

researchers induced multiple NASH mouse models through long-term feeding of HFHC or HFMCD, and found that hepatocyte-specific DUSP22 ablation (DUSP22HepKO) using the CRISPR/Cas9 system significantly aggravated liver steatosis, inflammation and fibrosis. However, AAV8-mediated DUSP22 overexpression (DUSP22HepOE) has a significant protective effect on NASH progression after high HFHC or HFMCD and is confirmed by lentivirus -mediated in vitro gene therapy for DUSP22.

At the same time, DUSP22 deletion or promotion did not affect the expression of other DUSPs, and DUSP22HepKO or DUSP22HepOE mice did not experience any NASH-related spontaneous liver phenotype under normal conditions. In-depth mechanism research of

shows that DUSP22 directly interacts with FAK, inhibiting its activation by dephosphorylation of Y397 and Y576 + Y577 residues of FAK, thereby inhibiting its downstream NF-κB and ERK1/2 signaling cascades. It was further found that the PTP motif containing the DUSP22 protein functional site (C88S) is required for FAK blockade.

Mechanism of action of DUSP22 in NASH-HCC

Therefore, by inhibiting the FAK signaling pathway , DUSP22 acts independently from other DUSPs and may be a promising therapeutic target for the treatment of NASH and its associated HCC.

Research Summary

03

In summary, the study provides further evidence for the protective effect of the DUSPs family on liver steatosis. For the first time, the study found that ROS-mediated degradation of DUSP22 is involved in the formation and progress of fatty liver. By promoting the phosphorylation of FAK on Y397 and Y576 + Y577 residues, it aggravates its downstream ERK1/2 and NF-κB signaling cascades, it participates in the pathogenesis of NASH and related HCC.

Reference materials:

https://www.nature.com/articles/s41467-022-33493-5

Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment plans. If you need health guidance, please go to a regular hospital for treatment.

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