Ivermectin Attenuates Methotrexate-Induced Liver Fibrosis by Reducing TGF-β and Syndecan-1 Expression

Background and Objectives: Methotrexate (MTX) is widely used in clinical settings but is often associated with hepatotoxic side effects, including oxidative stress, inflammation, and fibrosis. Novel therapeutic strategies are needed to mitigate MTX-induced liver injury. This study aimed to evaluate the hepatoprotective effects of ivermectin in a rat model of MTX-induced hepatotoxicity. Materials and Methods: Thirty male Wistar albino rats were randomly divided into three groups (n = 10 per group): control (saline only), MTX (single intraperitoneal dose of 20 mg/kg MTX), and MTX + ivermectin (20 mg/kg MTX + 0.5 mg/kg/day ivermectin for 10 days). At the end of the experiment, blood and liver tissues were collected for histopathological and biochemical evaluation, including ALT, malondialdehyde (MDA), TGF-β, and syndecan-1 levels. Results: MTX administration significantly increased plasma and hepatic MDA, TGF-β, syndecan-1, and ALT levels, alongside histological evidence of necrosis, fibrosis, and inflammatory infiltration (p < 0.001 vs. control). Ivermectin treatment significantly attenuated these alterations, with reductions in MDA (both plasma and liver), TGF-β, syndecan-1, and ALT levels (p < 0.05-0.001 vs. MTX). Histological scoring also revealed improved liver architecture and decreased necrosis, fibrosis, and leukocyte infiltration. Conclusions: Ivermectin demonstrates a strong hepatoprotective effect against MTX-induced liver injury, likely through antioxidant, anti-inflammatory, antifibrotic, and endothelial-protective mechanisms. These findings support the repurposing potential of ivermectin in mitigating drug-induced hepatic damage.