Novel Hepatoprotective Activity of Ivabradine Against Acute Liver Injury Is Associated with Modulation of SIRT1/Nrf2, AMPK, and mTOR Signaling Pathways

Background: Ivabradine, an inhibitor of funny current channels, is used in the management of sinus tachycardia. This work assessed the efficacy of ivabradine as a possible prophylactic candidate for acute liver injury (ALI) in mice. Methods: ALI was induced via acetaminophen (APAP) injection. Male Swiss Albino mice were allocated to six groups randomly, as follows: control, ivabradine control, APAP, NAC + APAP, ivabradine 10 + APAP, and ivabradine 20 + APAP. Ivabradine and NAC were given orally once daily for three successive days before the APAP challenge (with the final dose given 2 h before APAP). Different biochemical, pathological, immunohistochemical, and molecular assessments were adopted to evaluate the efficacy of ivabradine. Results: The significant elevation of the serum liver injury markers ALT, AST, and ALP, together with the significant histopathological alterations observed in hepatic tissues, confirmed the occurrence of APAP-induced ALI. APAP induced lipid peroxidation and depleted hepatic antioxidants, which were associated with significantly restrained endogenous antioxidative defense mechanisms of the hepatocytes, such as SIRT1/Nrf2. Additionally, APAP downregulated AMPK while inducing mTOR expression. Interestingly, pretreatment with ivabradine markedly attenuated APAP-induced hepatic injury, which was associated with restoration of hepatic SIRT1 and Nrf2 expression alongside favorable modulation of AMPK/mTOR signaling, along with significant reductions in hepatic MCP-1, CD68, and caspase-3 levels. Conclusions: Ivabradine exerts significant prophylactic hepatoprotection against APAP-provoked ALI in mice. These protective actions are associated with favorable modulation of SIRT1/Nrf2/Keap1 and AMPK/mTOR signaling alterations, though direct causal mediation remains to be confirmed via specific pathway-inhibition studies. Ivabradine may serve as a promising prophylactic candidate against drug-induced ALI.