What question did this study set out to answer?

To evaluate the hepatoprotective effects of Ambrisentan on dexamethasone-induced non-alcoholic steatohepatitis in rats.

May 26, 2026Open Access

Ambrisentan Exhibits Hepatoprotective Effects Against NASH-Associated Hepatic Injury in Dexamethasone-Treated Rats Through Regulation of Inflammation, Ferroptosis and Autophagy

Key Points

To evaluate the hepatoprotective effects of Ambrisentan on dexamethasone-induced non-alcoholic steatohepatitis in rats.
Rats were randomly divided into four groups: control, DEXA, and two AMB-treated groups receiving 5 or 10 mg/kg/day for one week along with DEXA.
Markers of liver function, lipid profile, and hepatic histopathological alterations were assessed post-experiment.
AMB at 10 mg/kg/day significantly improved liver function parameters, lipid profile, and histopathological features in DEXA-treated rats.
AMB reduced MDA, increased GSH, GPX4, and Nrf2, indicating reduced oxidative damage.
Downregulation of NF-κB, IL-6, and TGF-β1 was noted, suggesting decreased inflammation.

Abstract

Background/Objectives: Non-alcoholic steatohepatitis (NASH) represents a worldwide health challenge with limited currently available effective treatment. The present analysis was designed to examine possible therapeutic advances of Ambrisentan (AMB) targeting multiple features of hepatic damage in dexamethasone (DEXA)-provoked nonalcoholic steatohepatitis (NASH) in rats. Methods: Rats were randomly divided into four groups: a control group; a DEXA group; and two AMB-treated groups that received AMB (5 or 10 mg/kg/day orally for a week) before and concomitantly with DEXA (8 mg/kg/day, i.p.) for 6 days. After completion of the experiment, serum markers of liver function and lipid profile were assessed, and hepatic histopathological alterations were examined. Results: AMB (mainly at 10 mg/kg/day) markedly ameliorated liver-function parameters, the lipid profile, and hepatic histopathological characteristics in DEXA-treated rats. MDA was reduced, whereas GSH, GPX4 and Nrf2 were heightened, indicating elevated oxidative damage. Moreover, AMB efficiently reinstated iron homeostasis and aggravated iron overload by altering serum iron, hepatic ferritin, transferrin and hepcidin. AMB decreased serum calcium and hepatic calcineurin A levels, followed by a reduction in hepatic autophagy biomarker Beclin-1. AMB downregulated pro-inflammatory biomarkers NF-κB, IL-6 and TGF-β1. Moreover, it notably repressed the hepatic gene expression of ferritinophagy biomarker NCOA4, with elevated FTH1 hepatic gene expression. Moreover, AMB ameliorated DEXA-induced changes in endothelial and vascular function by increasing hepatic PGI2 and cGMP and lowering ET-1 and iNOS. Conclusions: AMB improved DEXA-induced NASH, primarily through its action on endothelin pathways, with associated reductions in inflammation and the downstream processes of ferroptosis, ferritinophagy, lipophagy, and autophagy.

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