Targeting sirtuin 1/nuclear factor erythroid 2-related factor 2/tumor necrosis factor-α pathway to modulate hepatic ischemia reperfusion-induced injury

doi:10.4254/wjh.v17.i12.110733

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World Journal of Hepatology

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1948-5182

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World J Hepatol. Dec 27, 2025; 17(12): 110733
Published online Dec 27, 2025. doi: 10.4254/wjh.v17.i12.110733

Targeting sirtuin 1/nuclear factor erythroid 2-related factor 2/tumor necrosis factor-α pathway to modulate hepatic ischemia reperfusion-induced injury

Mina Thabet Kelleni, Walaa Yehia Abdelzaher, Marly Adly, Mina Ezzat Attya, Michael A Fawzy, Mohamed Abdellah Ibrahim

Mina Thabet Kelleni, Walaa Yehia Abdelzaher, Marly Adly, Mohamed Abdellah Ibrahim, Department of Medical Pharmacology, College of Medicine, Minia University, Minia 61519, Egypt

Walaa Yehia Abdelzaher, Department of Pharmacology, Faculty of Oral and Dental Medicine, Lotus University, Minia 61768, Egypt

Mina Ezzat Attya, Department of Pathology, Minia University, Minia 61519, Egypt

Michael A Fawzy, Department of Biochemistry-Faculty of Pharmacy, Minia University, Minia 61519, Egypt

Author contributions: Kelleni MT, Abdelzaher WY, Adly M, and Ibrahim MA were responsible for conceptualization of the concept, performing the experiments, writing, and revising the manuscript; Attya ME performed and wrote the histopathological and immunohistochemical examination; Fawzy MA performed and wrote the western blotting. All authors read, revised, and approved the manuscript.

Institutional review board statement: Permission was received from the Study Ethics Committee of the Faculty of Medicine, Minia University (No. 585/2023).

Institutional animal care and use committee statement: The National Institutes of Health’s guide for the care and use of laboratory animals was followed during the research. All methods were done in accordance with the relevant ethical guidelines and regulations.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: All the necessary data are included in the manuscript. Any further data will be made available upon a reasonable request.

Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Corresponding author: Mina Thabet Kelleni, MD, PhD, Assistant Professor, Department of Medical Pharmacology, College of Medicine, Minia University, Main Road Shalaby Land, Minia 61519, Egypt. mina.kelleni@mu.edu.eg

Received: June 13, 2025
Revised: July 24, 2025
Accepted: November 7, 2025
Published online: December 27, 2025
Processing time: 196 Days and 10.7 Hours

Abstract

BACKGROUND

Hepatic ischemia reperfusion (HIR) injury is a major complication affecting various major liver surgeries, including liver transplantation. Aprepitant (APRE), a neurokinin-1 receptor antagonist, is commonly used as an antiemetic to prevent chemotherapy-induced nausea and vomiting.

AIM

To assess the potential protective effect of APRE against HIR-induced liver injury via targeting the nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing receptor 3/interleukin (IL)-1beta signaling pathway.

METHODS

Six groups of adult male Wistar albino rats were divided as follows: Sham group, Sham/APRE10 group (APRE 10 mg/kg), HIR group, HIR/APRE5 group (APRE 5 mg/kg), HIR/APRE10 group (APRE 10 mg/kg), and HIR/APRE20 group (APRE 20 mg/kg). Serum alanine transaminase, aspartate transaminase, liver malondialdehyde, total antioxidant capacity levels, as well as IL-6, sirtuin 1 (Sirt1), caspase-3, cleaved caspase-3, and tumor necrosis factor alpha biomarkers, were evaluated. Hepatic specimens were examined histopathologically and immunohistochemically for nuclear factor erythroid-2-related factor 2 (Nrf2) immunoexpression.

RESULTS

HIR resulted in hepatic damage, as evidenced by histopathological changes and a significant increase in serum alanine transaminase, aspartate transaminase, hepatic malondialdehyde, caspase-3, and tumor necrosis factor alpha levels. Additionally, there were significant increases in hepatic total antioxidant capacity and reductions in IL-6 and cleaved caspase-3 protein levels, as demonstrated by Western blot analysis, along with enhanced immunoexpression of Sirt1 and Nrf2. APRE has significantly reduced various parameters of oxidative stress, inflammation, and apoptosis, and a significant increase in liver Nrf2 immunoexpression, leading to a significant improvement in the histopathological changes.

CONCLUSION

In conclusion, targeting the Sirt1/Nrf2 signaling pathway, as demonstrated by APRE in our model, could present a promising therapeutic target to protect against HIR-induced liver injury during major liver surgeries.

Keywords: Hepatic ischemia reperfusion injury; Aprepitant; Sirtuin 1; Nuclear factor erythroid-2-related factor 2; Tumor necrosis factor alpha

Core Tip: This study demonstrates that aprepitant, a neurokinin-1 receptor antagonist, exerts hepatoprotective effects in a rat model of hepatic ischemia reperfusion by modulating the sirtuin 1/nuclear factor erythroid-2-related factor 2/tumor necrosis factor alpha signaling pathway. Aprepitant significantly reduced hepatic enzyme elevation, oxidative stress parameters, inflammatory cytokines, and apoptosis markers, while enhancing the pluripotent capacity of sirtuin 1/nuclear factor erythroid-2-related factor 2 expression, highlighting its potential as a therapeutic agent to mitigate HIR-induced liver injury during major liver surgeries, as well as highlighting the significant therapeutic pharmacological potential while targeting this pathway by other current and future drugs.