Targeting Jun N-terminal kinase phosphorylation: A human-derived hepatoprotective peptide human liver transplantation peptide 1 attenuates hepatic ischemia-reperfusion injury

doi:10.3748/wjg.v32.i3.113935

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Jan 21, 2026 (publication date) through Jan 18, 2026

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World Journal of Gastroenterology

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1007-9327

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World J Gastroenterol. Jan 21, 2026; 32(3): 113935
Published online Jan 21, 2026. doi: 10.3748/wjg.v32.i3.113935

Targeting Jun N-terminal kinase phosphorylation: A human-derived hepatoprotective peptide human liver transplantation peptide 1 attenuates hepatic ischemia-reperfusion injury

Hui-Wen Xie, Qun Bao, Zi-Xuan Chen, Xiang-Min Zhang, Xi-Yu Liu, Rui Wang, Yue-Song Cai, Peng Sun

Hui-Wen Xie, Zi-Xuan Chen, Xi-Yu Liu, Department of Medicine, Shanghai Jiao Tong University, Shanghai 200336, China

Qun Bao, Peng Sun, Department of General Surgery, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China

Xiang-Min Zhang, Department of Anesthesiology, Shanghai Changning Maternity and Infant Health Hospital, Shanghai 200336, China

Rui Wang, Hongqiao International Institute of Medicine, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China

Yue-Song Cai, College of Medicine, Yanbian University, Yanbian 133002, Jilin Province, China

Co-first authors: Hui-Wen Xie and Qun Bao.

Author contributions: Xie HW and Bao Q made equal contributions as co-first authors; Sun P, Bao Q, and Xie HW designed the research study and supervised data collection; Xie HW, Zhang XM, Liu XY, and Cai YS contributed to the experimental execution; Xie HW was responsible for data analysis and drafting of the initial manuscript; Bao Q and Chen ZX contributed to the provided experimental guidance; Chen ZX, Sun P, and Wang R participated in revision and proofreading. All authors have thoroughly reviewed and concurred with the final, published version of the manuscript.

Supported by National Natural Science Foundation of China, No. 82070634; National Key Research and Development Program of China, No. 2021YFC2701900; Natural Science Foundation of Shanghai Municipality, No. 23ZR1458200; Shanghai Sixth People’s Hospital Medical Group, No. ly202401; and the Shanghai Jiao Tong University Cross Disciplinary Translational Foundation, No. YG2022QN117.

Institutional review board statement: This study was approved by the Ethical Committee of Shanghai Tong Ren Hospital, No. 2021-089-01; and Ethical Committee of Huashan Hospital Affiliated to Fudan University, No. KY2021-856.

Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Shanghai Tong Ren Hospital, No. AF/SQ-14/04.0.

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 data generated during this study are available from the corresponding authors upon 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: Peng Sun, Department of General Surgery, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, No. 1111 Xianxia Road, Shanghai 200336, China. surgeonpeng@foxmail.com

Received: September 8, 2025
Revised: October 1, 2025
Accepted: November 25, 2025
Published online: January 21, 2026
Processing time: 131 Days and 15.2 Hours

Abstract

BACKGROUND

Hepatic ischemia-reperfusion injury (HIRI) is a major complication in liver transplantation with limited treatment options. Peptidomics offers a promising approach to discover therapeutic peptides.

AIM

To identify novel peptides from human liver transplants that could mitigate HIRI and preliminarily explore their mechanisms.

METHODS

Liver samples from six transplant patients were analyzed using nano-liquid chromatography-tandem mass spectrometry. A candidate peptide, human liver transplantation peptide 1 (HLTP1), was screened in a murine HIRI model and validated in vitro using AML12 cells. Mechanisms were probed via Jun N-terminal kinase (JNK) phosphorylation analysis and rescue experiments with a JNK activator.

RESULTS

HLTP1 was identified as a protective peptide. It reduced liver damage and apoptosis in mice, enhanced cell viability and proliferation, and decreased apoptosis in AML12 cells. Mechanistically, HLTP1 inhibited JNK phosphorylation, and its effects were reversed by JNK activation.

CONCLUSION

HLTP1 alleviates HIRI by inhibiting JNK-mediated apoptosis, representing a potential therapeutic strategy for liver transplantation.

Keywords: Hepatic ischemia-reperfusion injury; Peptidomics; Peptide; Apoptosis; Jun N-terminal kinase phosphorylation

Core Tip: This study pioneers the discovery of a novel endogenous peptide, human liver transplantation peptide 1, directly from clinical human liver transplant samples using peptidomics. We demonstrate that human liver transplantation peptide 1 confers significant protection against hepatic ischemia-reperfusion injury by specifically inhibiting Jun N-terminal kinase phosphorylation and subsequent hepatocyte apoptosis. This work is the first to identify a therapeutically promising peptide of human origin with this mechanism for hepatic ischemia-reperfusion injury, offering a highly translatable and innovative strategy to improve outcomes in liver transplantation and other ischemic liver conditions.