Doxorubicin-induced hepatic toxicity in rats: Mechanistic protective role of Omega-3 fatty acids through Nrf2/HO-1 activation and PI3K/Akt/GSK-313 axis modulation

Doxorubicin (DOX), a common antibiotic used to treat a variety of tumors, has several substantial adverse effects that limit its clinical use. As a result, finding effective protective agents to combat DOX-induced organ damage is a necessity. The current study was set to delineate the hepatoprotective role of omega-3 fatty acids (co-3FA) against DOX-mediated acute liver damage in rats and the underlined mechanism of GSK-313 inhibition. Five groups of rats were orally received either saline (groups 1 & 2) or co-3FA (25, 50 and 100 mg/kg/day; groups 3, 4 & 5, respectively) for 28 consecutive days. Single DOX intraperitoneal injection (20 mg/kg) was used to induce hepatic toxicity in all groups except group 1 (negative control). Blood samples and liver tissues were collected 48-hr after injection. Our results revealed that pre-administration of co-3FA (25, 50 and 100 mg/kg) to DOX-induced hepatic injured rats showed a significant reduction in serum hepatic injury biomarkers (ALT, AST, total and direct bilirubin) as well as hepatic contents of MDA, GSH, Nrf2 and HO-1. Additionally, hepatic PI3K, pAkt and GSK-313 have been restored significantly in a dose-dependent manner. Furthermore, all the hepatic histopathological features have been retained upon co-3FA treatment together with the immunostaining intensity of tumor necrosis factor-a and caspase-3. These results suggest that co-3FA have shown a marked activation of the Nrf2/HO-1 signaling pathway and modulation of the PI3K/pAkt/GSK-313 axis against DOX-induced hepatotoxicity.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study aimed to investigate the protective effect of omega-3 fatty acids (co-3FA) against DOX-induced acute liver damage and the underlying mechanism. The results showed that pre-administration of co-3FA can alleviate DOX-induced liver injury and affect multiple indicators and signaling pathways related to liver damage.