Liver fibrosis is an integral form of chronic liver disease (CLD). The characteristic of Liver fibrosis is the formation of a fibrous scar from excessive deposition of extracellular matrix (ECM) proteins. This fibrous scar results in distortion of hepatic architecture and liver stiffness. However, Chronic liver diseases are a major global health burden and account for approximately 2 million deaths per year worldwide. In addition, the level of fibrosis correlates with liver function and represents the major risk factor for development of hepatocellular carcinoma (HCC). Consequently, liver cirrhosis is currently the 11th most common cause of death in the world and the fourth most frequent cause of death in adults in central Europe. Next, we will introduce a potent antifibrotic agent and PI3K/ERK pathway inhibitor — CXJ-2.
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CXJ-2 is a cyclic peptide, with potent antifibrotic efficacy (inhibits EDPs-EBP interaction).
In addition, CXJ-2 exhibits moderate affinity toward elastin derived peptides (EDPs). Also, CXJ-2 inhibits PI3K/ERK pathway.
In vitro experiments, CXJ-2 (10 μM , 24 h) decreases α-SMA expression in a dose-dependent manner in LX2 cells. Moreover, CXJ-2 (10 μM , 24 h) exhibits potent inhibition activity against HSC activation, proliferation, and migration in an LX2 cell model.
In addition, CXJ-2 also exerts a good activity when in vitro experiments. CXJ-2 (150 μg/kg, i.p.; single daily for 3 weeks) can effectively ameliorate collagen accumulation in a CCl4-induced liver fibrosis mouse model. Another very important point is that CXJ-2 (0.1 mg/kg; s.c.; single dose) shows favorable pharmacokinetic properties.
CXJ-2 with improved serum stability and in vivo clearance profile. In addition, CXJ-2 with a longer half-life. That is to say, CXJ-2 can provide a promising drug candidate for the treatment of liver fibrosis in the future.
All in all, CXJ-2 is a hopeful agent for research of liver fibrosis.
Reference:
[1] Song N, et al. J Med Chem. 2023 Apr 13;66(7):4689-4702.
[2] Roehlen N, et al. Cells. 2020 Apr 3;9(4):875.