Epigallocatechin Gallate Induces Hepatic Stellate Cell Senescence and Attenuates Development of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a highly morbid condition with lack of effective treatment options. HCC arises from chronically inflamed and damaged liver tissue; therefore, chemoprevention may be a useful strategy to reduce HCC incidence. Several reports suggest that Epigallocatechin gallate (EGCG), extracted from green tea, can suppress liver inflammation and fibrosis in animal models, but its role in HCC chemoprevention is not well established. In this study, male Wistar rats were injected with DEN at 50 mg/kg for 18 weeks to induce cirrhosis and HCC, and EGCG was given in drinking water at a concentration of 0.02%. Clinically achievable dosing of EGCG was well tolerated in DEN-injured rats and was associated with improved serum liver markers including ALT, AST, and total bilirubin, and reduced HCC tumor formation. Transcriptomic analysis of DEN-injured hepatic tissue was notable for increased expression of genes associated with the Hoshida high risk HCC gene signature, which was prevented with EGCG treatment. EGCG treatment also inhibited fibrosis progression, which was associated with inactivation of hepatic stellate cells (HSCs) and induction of the senescenceassociated secretory phenotype (SASP). In conclusion, EGCG administered at clinically safe doses exhibited both chemopreventive and anti-fibrotic effects in a rat DEN liver injury model.