LECT2/Tie1/Src signaling regulates the oxidative stress response in endothelial cells and liver ischemia-reperfusion injury

doi:10.4254/wjh.119561

Advanced Search

BPG is committed to discovery and dissemination of knowledge

Home / Archive / Volume 18, Issue 6

This Article

(6)

(8)

(0)

(37)

Peer-Review Report of This Article

CrossCheck and Google Search of This Article

Academic Rules and Norms of This Article

Citation of this article

Corresponding Author of This Article

Research Domain of This Article

Article-Type of This Article

Open-Access Policy of This Article

Times Cited Counts in Google of This Article

Journal Information of This Article

Publication Name

World Journal of Hepatology

ISSN

1948-5182

Publisher of This Article

Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study

Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Hepatol. Jun 27, 2026; 18(6): 119561
Published online Jun 27, 2026. doi: 10.4254/wjh.119561

LECT2/Tie1/Src signaling regulates the oxidative stress response in endothelial cells and liver ischemia-reperfusion injury

Yu Yang, Shi-Li Wu, Zhi-Hao Huang, Meng-Qi Dong, Zhi-Min Liu, Meng Xu, Yi Gao, Wei-Jie Zhou, Yuan Lin

Yu Yang, Shi-Li Wu, Zhi-Hao Huang, Meng-Qi Dong, Zhi-Min Liu, Meng Xu, Wei-Jie Zhou, Yuan Lin, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China

Yi Gao, General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China

Author contributions: Lin Y and Zhou WJ contributed to conceptualization, resources, supervision, and writing of original drafts; Yang Y, Wu SL, Huang ZH, Liu ZM, Dong MQ, and Xu M contributed to methodology and investigation; Yang Y, Huang ZH, and Dong MQ contributed to validation; Yang Y and Dong MQ contributed to formal analysis; Lin Y, Gao Y, and Zhou WJ contributed to data curation; Yang Y and Lin Y contributed to visualization; Lin Y contributed to project administration; Lin Y, Xu M, and Zhou WJ contributed to funding acquisition; and all authors reviewed and edited the manuscript, and approved the final version to publish.

Supported by National Key Research and Development Program, No. 2022YFA1106700; and National Natural Science Foundation of China, No. 82270645, No. 82570748, No. 82200633, and No. 92068206.

Institutional animal care and use committee statement: This study was approved by the Animal Ethics Committee of Nanfang Hospital, No. NFYY-2018-031.

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: The data and materials of this study are available from Lin Y and Zhou WJ upon reasonable request.

Corresponding author: Yuan Lin, PhD, Professor, Department of General Surgery, Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Road, Guangzhou 510515, Guangdong Province, China. xiaoyuanlinz@163.com

Received: February 2, 2026
Revised: February 24, 2026
Accepted: April 17, 2026
Published online: June 27, 2026
Processing time: 147 Days and 6.7 Hours

Abstract

BACKGROUND

Hepatic ischemia-reperfusion injury (IRI) is a critical pathological process associated with trauma, sepsis, and liver surgeries, including transplantation. During reperfusion, oxidative stress in sinusoidal endothelial cells triggers cell death, however, the underlying regulatory mechanisms remain poorly defined. Previous studies have implicated leukocyte-derived chemotaxin-2 (LECT2) in various diseases and identified it as a ligand for the orphan receptor Tie1, yet its role in endothelial cell injury during liver IRI remains unclear.

AIM

To investigate whether LECT2 exacerbates liver IRI by regulating oxidative stress in endothelial cells through the Tie1/Src signaling pathway and to evaluate the therapeutic potential of targeting this axis.

METHODS

In vitro hypoxia-reoxygenation injury was modeled in EA.hy926 endothelial cells, followed by LECT2 knockdown or recombinant LECT2 treatment, Tie1 silencing, and Tie1-Ig3 segment protein treatment to block LECT2/Tie1 binding. Src kinase activity was inhibited using dasatinib. Cell viability, oxidative stress, cytotoxicity, and signaling pathway activation were assessed. In vivo, LECT2 knockout mice underwent hepatic ischemia-reperfusion, while injury markers, inflammatory cytokines, and endothelial damage were evaluated.

RESULTS

LECT2 knockdown reduced oxidative stress and endothelial cell damage following hypoxia-reoxygenation, whereas recombinant LECT2 exacerbated these effects. Disruption of LECT2/Tie1 binding, via either Tie1 knockdown or Tie1-Ig3 treatment mitigated injury. Mechanistically, LECT2 activated Src kinase phosphorylation in a Tie1-dependent manner, and Src inhibition reversed LECT2-induced cell damage. In mice, LECT2 deletion attenuated liver IRI, decreased apoptosis and inflammation, and better preserved sinusoidal endothelial integrity.

CONCLUSION

The LECT2/Tie1/Src signaling axis plays a critical role in regulating oxidative stress and endothelial cell injury during hepatic ischemia-reperfusion. Targeting the LECT2/Tie1/Src signaling pathway may offer a novel therapeutic strategy for mitigating liver IRI in clinical settings.

Keywords: Leukocyte-derived chemotaxin-2; Tie1; Src kinase; Endothelial cells; Oxidative stress; Ischemia-reperfusion injury; Liver injury

Core Tip: This study elucidates a novel signaling mechanism in which leukocyte-derived chemotaxin-2 exacerbates hepatic ischemia-reperfusion injury by binding to Tie1 and activating Src kinase, thereby amplifying oxidative stress and endothelial cell damage. Targeting the leukocyte-derived chemotaxin-2/Tie1/Src axis represents a promising therapeutic strategy for mitigating liver ischemia-reperfusion injury, offering potential translational applications in liver surgery and transplantation.