Growth arrest specific 6 ameliorated inflammation and portal pressure through activating efferocytosis in cholestasis and portal hypertension

doi:10.3748/wjg.v32.i20.116020

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Publication Name

World Journal of Gastroenterology

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1007-9327

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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 Gastroenterol. May 28, 2026; 32(20): 116020
Published online May 28, 2026. doi: 10.3748/wjg.v32.i20.116020

Growth arrest specific 6 ameliorated inflammation and portal pressure through activating efferocytosis in cholestasis and portal hypertension

Gu-Qing Luo, Jin-Bo Zhao, Zheng-Hao Wu, Jia-Yun Lin, Chi-Hao Zhang, Guang-Bo Wu, Qiang Fan, Xiao-Liang Qi, Hong-Jie Li, Meng Luo, Lei Zheng

Gu-Qing Luo, Jin-Bo Zhao, Zheng-Hao Wu, Jia-Yun Lin, Chi-Hao Zhang, Guang-Bo Wu, Qiang Fan, Xiao-Liang Qi, Hong-Jie Li, Meng Luo, Lei Zheng, Department of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China

Co-first authors: Gu-Qing Luo and Jin-Bo Zhao.

Co-corresponding authors: Meng Luo and Lei Zheng.

Author contributions: Luo GQ, Zhao JB, Zheng L, Luo M contributed to conceptualization, methodology, validation, project administration; Lin JY, Zhang CH, Wu GB contributed to software, data curation; Fan Q and Qi XL contributed to investigation, data curation; Luo GQ, Wu ZH, Zheng L and Li HJ contributed to writing - original draft, formal analysis; Luo GQ, Zheng L and Luo M contributed to writing - review & editing, visualization; Luo M, Zheng L and Li HJ contributed to supervision; Zheng L, Zhang CH, Luo M and Lin JY contributed to funding acquisition; and all authors read and approved the final manuscript. Both Zheng L and Luo M have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors. Both of them applied for and obtained the funds for this research project. Zheng L conceptualized, designed, and supervised the whole process of the project. He searched the literature, revised and submitted the early version of the manuscript. Luo M was instrumental and responsible for data re-analysis and re-interpretation, figure plotting, and comprehensive literature search. This collaboration between Zheng L and Luo M is crucial for the publication of this manuscript and other manuscripts still in preparation.

Supported by Postdoctoral Scientific Research Foundation of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 202401023; Shanghai Municipal Commission of Health and Family Planning, No. 20244Y0195 and No. 20234Y0132; and National Natural Science Foundation of China, No. 82100639, No. 82200630 and No. 81970526.

Institutional animal care and use committee statement: This study was approved by the Ethics Committee of Shanghai Ninth People’s Hospital, No. SH9H-2024-A089-SB.

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 in the current study are available from the corresponding author upon reasonable request.

Corresponding author: Lei Zheng, MD, PhD, Department of General Surgery, Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, No. 639 Zhizaoju Road, Huangpu District, Shanghai 200011, China. zl1055174020@163.com

Received: October 31, 2025
Revised: December 31, 2025
Accepted: February 28, 2026
Published online: May 28, 2026
Processing time: 201 Days and 8.7 Hours

Abstract

BACKGROUND

Portal hypertension (PHT) is a complication of chronic liver disease. PHT was observed from the early stage of cholestatic liver disease (CLD). Growth arrest specific 6 (Gas6)-mediated macrophage efferocytosis was an essential process clearing apoptotic cells and facilitating liver injury repair.

AIM

To investigate the effects of recombinant Gas6 (rGas6) on efferocytosis in PHT based on mice models of cholestasis.

METHODS

The cholestasis models were established by bile duct ligation (BDL) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. rGas6 was intra-peritoneally injected to induce macrophage efferocytosis. Portal pressure (PP) was determined and subsequent evaluations of liver injury, inflammation, fibrosis, and efferocytosis were performed. RAW264.7 cells, Jurkat cells, and human liver sinusoidal endothelial cells (hLSECs) were used to investigate the role of Gas6-mediated efferocytosis in PHT in vitro.

RESULTS

Both BDL and DDC models exhibited remarkable elevations in PP, accompanied with significant liver injury, inflammation, and fibrosis. The macrophage efferocytosis was also defected in BDL and DDC mice. Administration of rGas6 promoted macrophage efferocytosis via phosphorylation of MerTK, which reduced apoptotic cells and increased reparative macrophages in liver. It further lowered PP and ameliorated hepatic inflammation, while fibrosis was not significantly alleviated or exacerbated. In vitro study confirmed the enhancement of macrophage efferocytosis upon rGas6 treatment, accompanied with a transition to reparative phenotype. Moreover, efferocytotic macrophage mitigated hLSEC injury and defenestration.

CONCLUSION

BDL- and DDC-induced cholestasis mice exhibited significant PHT and defective efferocytosis. rGas6-mediated activation of MerTK enhanced macrophage efferocytosis, which cleared apoptotic cells, alleviated hepatic inflammation, and eventually ameliorated intrahepatic vascular resistance and PP.

Keywords: Portal hypertension; Cholestatic liver disease; Growth arrest specific 6; Efferocytosis; MER proto-oncogene; Tyrosine kinase

Core Tip: The current study revealed that defective efferocytosis was related to portal hypertension (PHT) in mice model of cholestasis. Administration of recombinant growth arrest specific 6 (Gas6) ameliorated elevated intrahepatic vascular resistance and portal pressure in cholestasis. Gas6 enhanced macrophage efferocytosis by activating MerTK, which relieved inflammation and eventually alleviated liver sinusoidal endothelial cell dysfunction and PHT.