The potential hepatoprotective effect of Erythropoietin against liver damage induced by Doxorubicin through modulation of PI3K/Akt/GSK3β and activation of Nrf2/HO-1 pathway

Abstract

This study aims to evaluate the hepatoprotective effect of erythropoietin against doxorubicin-induced liver damage in a male rat model through PI3K/Akt/GSK3β axis modulation and activation of the Nrf2/HO-1 pathway. Doxorubicin, a chemotherapeutic antibiotic used to treat many types of cancer, has some considerable side effects that limit its clinical use, including hepatotoxicity. Erythropoietin is a glycoprotein hormone primarily recognized for its crucial function in promoting erythropoiesis. Recent studies have demonstrated the significant cytoprotective effects of erythropoietin in several organs. Thirty-six male Wistar rats were randomly separated into six groups: (Group 1) a negative control group; (Group 2) a doxorubicin induction group; (Groups 3, 4, and 5) three groups pre-treated with erythropoietin in three different doses (1000, 3000, and 6000 IU/kg); and (Group 6) a positive control group pre-treated with silymarin (100 mg/kg). On the 7th day, all groups (except group 1) were injected with a single dose of doxorubicin (20 mg/kg). On day 9 of the experiment, blood and liver samples were taken for subsequent analysis. The results showed that erythropoietin pre-treatment significantly reduced doxorubicin-induced hepatotoxicity by stimulating the PI3K/Akt and Nrf2/HO-1 pathways and suppressing GSK3β and caspase 3. In addition to that, erythropoietin pre-treatment also raised the levels of GSH, lowered the levels of MDA, and brought the levels of the liver enzymes ALT and AST back to normal compared to the induction group. In conclusion, via modulating PI3K/Akt/GSK3β and activating the Nrf2/HO-1 pathway, erythropoietin pre-treatment protected the liver against hepatotoxicity caused by doxorubicin in a dose-dependent manner.