Editor's Note
Astragalus has been used for centuries in traditional Chinese medicine for the prevention and treatment of diseases such as diabetes and cancer. Commonly combined with other herbs, astragalus has been promoted as a treatment for many conditions, including upper respiratory infections, hay fever, asthma, chronic fatigue syndrome, and chronic kidney disease, among others. It’s also promoted to strengthen and regulate the immune system. 
 
Astragaloside IV (AS-IV), one of the main bioactive compounds of astragalus, has a wide range of pharmacological effects including anti-inflammation and anti-cancer effects. Researchers here investigated effects of AS-IV in an induced primary liver cancer mouse model. In vivo assays included liver biopsy, histopathology and post-mortem analysis included immunohistochemistry, immunofluorescent, and Western blotting analysis, and in vitro assays included immunofluorescent, and Western blotting analysis. Results show AS-IV significantly inhibited the development of primary liver cancer. Researchers propose a regulatory mechanism and suggest further clinical studies on astragalus and extracted compounds.
Abstract

Ethnopharmacological relevance
Astragalus is a medicinal herb used in China for the prevention and treatment of diseases such as diabetes and cancer. As one of the main active ingredients of astragalus, Astragaloside IV (AS-IV) has a wide range of pharmacological effects, including anti-inflammation and anti-cancer effects.

Aim of the study
Different phosphorylated forms of Smad3 differentially regulate the progression of hepatic carcinoma. The phosphorylation of the COOH-terminal of Smad3 (pSmad3C) and activation of the Nrf2/HO-1 pathway inhibits hepatic carcinoma, while phosphorylation of the linker region of Smad3 (pSmad3L) promotes progression. Thus, pSmad3C/3L and Nrf2/HO-1 pathways are potential targets for drug of anti-cancer development. AS-IV is anti-apoptotic and can inhibit hepatocellular carcinoma cell (HCC) proliferation, invasion, and tumor growth in nude mice. However, it is not clear whether AS-IV has a therapeutic effect on inhibiting the progression of primary liver cancer by regulating the pSmad3C/3L and Nrf2/HO-1 pathway. The purpose of this study is to investigate whether AS-IV inhibits hepatocellular carcinoma by regulating pSmad3C/3L and Nrf2/HO-1 pathway.

Materials and methods
primary liver cancer in mice induced by DEN/CCl4/C2H5OH (DCC) and HSC-T6/HepG2 cell models activated by TGF-β1 was investigated for the mechanisms of AS-IV. In vivo assays included liver biopsy, histopathology and post-mortem analysis included immunohistochemistry, immunofluorescent, and Western blotting analysis, and in vitro assays included immunofluorescent, and Western blotting analysis.

Results
AS-IV significantly inhibited the development of primary liver cancer, reflecting improved liver biopsy, histopathology. The incidence and multiplicity of primary liver cancer were markedly decreased by AS-IV treatment at the 20th week. AS-IV had observable effects on the TGF-β1/Smad and Nrf2/HO-1 expression in vivo, especially up-regulated pSmad3C, pNrf2, HO-1, and NQO1, while it down-regulated pSmad2C, pSmad2L, pSmad3L, PAI-1, and α-SMA at the 12th week and the 20th week. Furthermore, in vitro analysis further confirmed that AS-IV regulated the expression of pSmad3C/3L and Nrf2/HO-1 pathway in HSC-T6 and HepG2 cells activated by TGF-β1.

Conclusion
AS-IV administration delays the occurrence of primary liver cancer by continually suppressing the development of fibrosis, the mechanism of the therapeutic effect involving the regulation of the pSmad3C/3L and Nrf2/HO-1 pathways, especially in regulation reversibility and antagonism of pSmad3C and pSmad3L and promoting the phosphorylation of Nrf2.

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