Pomegranate peel extract ameliorates liver fibrosis induced by carbon tetrachloride in rats through suppressing p38MAPK/Nrf2 pathway

Hepatic fibrosis is a chronic process characterized by excessive production of extracellular matrix in response to liver injury, which eventually leads to cirrhosis and even death. Growing evidence has demonstrated that pomegranate could efficiently reduce liver fibrosis in rats. Previous studies have also shown that Nrf2 activation alleviated liver fibrosis. However, whether the MAPK-Nrf2 pathway were involved in the protective effect of extracts from pomegranate peels (EPP) on carbon tetrachloride (CCl4)-induced hepatic fibrosis remains elusive. The hepatic fibrosis model was established by injection with 50% CCl4 subcutaneously in male SD rats twice a week for four weeks. After four weeks, EPP and/or signaling inhibitors were administered every day for 4 weeks, respectively. The protective effects of EPP on liver function, oxidative markers, and liver fibrosis were determined. The results showed that EPP treatment decreased MDA levels, enhanced GSH-Px activities, inhibited the development of hepatic fibrosis evidenced by reduced TGF-beta and collagen1-alpha 2 levels as well as fibrosis areas, improved liver function in CCl4 injury rats. Similarly, p38MAPK inhibitor SB203580 produced the protective effect as EPP in the setting of rat model. Moreover, Nrf2 inhibitor ML385 did not affect the inhibitory effect of EPP on p38MAPK activity, which indicates that Nrf2 might be a downstream molecule of p38MAPK in the protective mechanism of EPP against hepatic fibrosis. In conclusion, EPP displays a protective effect against liver fibrosis induced by CCl4, and its underlying mechanisms might be associated with suppressing p38MAPK-Nrf2 signaling pathway.