# Ivabradine Attenuates Experimental Hepatic Fibrosis by Modulating Inflammatory and Apoptotic Signaling Pathways

## TL;DR

Ivabradine reduces liver fibrosis in rats by improving liver function and reducing inflammation and cell death.

## Contribution

This study demonstrates ivabradine's novel antifibrotic effects in a rat model of hepatic fibrosis.

## Key findings

- Ivabradine improved liver enzymes and antioxidant balance in TAA-treated rats.
- Ivabradine suppressed NF-κB and TGF-β pathways, reducing fibrosis.
- The drug normalized apoptotic markers and inhibited collagen deposition.

## Abstract

Background: Hepatic fibrosis and its progressive form, liver cirrhosis, are dangerously recognized complications of liver injury with limited treatment options. This study evaluated the hepatoprotective effects of ivabradine on thioacetamide (TAA)-induced hepatic fibrosis in rats. Methods: Rats were divided into five groups with 10 rats/group and treated as follows: normal, where rats received 0.5% CMC-Na solution orally; ivabradine control, where rats received only ivabradine (20 mg/kg, once daily, orally) for 6 weeks; TAA, where rats received an intraperitoneal (i.p.) injection of TAA (200 mg/kg) thrice weekly for 6 weeks and daily oral 0.5% CMC-Na solution, and two ivabradine + TAA groups, where two doses of ivabradine were tested. Low (10 mg/kg) and high (20 mg/kg) doses of ivabradine were orally given once daily to each group for 6 weeks concurrently with TAA injection. Results: TAA caused marked elevations in liver enzymes, increased MDA, depletion of antioxidant defenses, activation of NF-κB p65 and pro-inflammatory cytokines, dysregulation of apoptotic markers, and upregulation of the PI3K/AKT/mTOR and TGF-β pathways, accompanied by extensive collagen deposition. Ivabradine produced dose-dependent improvements in biochemical markers of liver function, restored oxidant/antioxidant balance, suppressed NF-κB p65/TNF-α, normalized Bax/Bcl-2/caspase-3 expression, and inhibited PI3K/AKT/mTOR as well as TGF-β signaling, leading to significant attenuation of fibrosis. Conclusions: The current findings indicate that ivabradine exerts potent antioxidant, anti-inflammatory, anti-apoptotic, and antifibrotic actions against TAA-induced hepatic fibrosis. Future clinical studies are recommended to determine whether these protective effects translate to patients with chronic liver disease.