Thioacetamide-induced hepatotoxicity in rats: Hepatoprotective role of ethyl gallate in association with the regulation of Nrf2/MAPK/NF-κB signaling pathway.

Acute liver injury (ALI) is characterized by the rapid onset of liver dysfunction, which may progress to acute liver failure within a short period. Thioacetamide (TAA) is widely known to induce hepatotoxicity through mechanisms involving oxidative stress, cell death, inflammation, fibrosis, and cirrhosis. Ethyl gallate (EG), a polyphenolic compound, is recognized for its potent antioxidant and free radical scavenging properties. The present study investigated the hepatoprotective role of EG on TAA-induced ALI through the Nrf2/MAPK/NF-κB associated signaling pathways in rats. Female Wistar rats were divided into six groups (n = 6) as control, TAA (350 mg/kg, i.p.,), TAA + EG (10 & 20 mg/kg, p.o.,), TAA + silymarin (SIL) (100 mg/kg, p.o.,) and EG (20 mg/kg, p.o.,). TAA, EG, and SIL were administered as a single dose, and animals were euthanized 24 h after treatment. TAA administration caused a significant elevation in serum liver marker enzymes, as well as oxidative stress and inflammatory markers in liver tissue, indicating the onset of ALI. Co-treatment with EG and SIL significantly reduced elevated liver enzymes and oxidative stress markers, while restoring hepatic antioxidant status. Both treatments downregulated MAPK signaling pathway and NF-κB signaling pathway, and upregulated Nrf2 signaling pathway markers. Notably, high-dose EG (20 mg/kg) markedly prevented hepatocellular damage in TAA-induced rats. Overall, the findings of this study demonstrate the hepatoprotective potential of EG against TAA-induced acute liver injury through modulation of Nrf2 (sMaf, NQO1, Keap1, and Cul3), MAPK (JNK1, c-Jun, ERK1, ASK1, p38, and Bcl2), and NF-κB signaling pathways in rats.