Specificity protein 1/ZIP8/zinc axis reduced macrophage extracellular traps to alleviate severe acute pancreatitis in mice

doi:10.3748/wjg.118814

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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

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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. Oct 14, 2026; 32(38): 118814
Published online Oct 14, 2026. doi: 10.3748/wjg.118814

Specificity protein 1/ZIP8/zinc axis reduced macrophage extracellular traps to alleviate severe acute pancreatitis in mice

Yi-Miao Cheng, Qiong Liu, Zu-Xing Wei, Xiao-Yan Qi, Jun He, Xu-Yang Hou

Yi-Miao Cheng, Zu-Xing Wei, Xiao-Yan Qi, Jun He, Xu-Yang Hou, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China

Qiong Liu, Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China

Xu-Yang Hou, Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China

Author contributions: Hou XY designed the study, developed the methodology, and provided critical revisions; Cheng YM conducted the experiments, collected the data, performed statistical analyses, and drafted the initial manuscript; Liu Q, Wei ZX, Qi XY, and He J contributed to assisting with the experiments and interpreting the results.

Supported by the Natural Science Foundation of Hunan Province, No. 2023JJ40821; Natural Science Foundation of Changsha City, No. kq2208308; and Hunan Provincial Health Commission Health Research Project, No. W20243029.

Institutional review board statement: This study did not involve human participants, human tissues, or identifiable human data.

Institutional animal care and use committee statement: This study followed standard ethical guidelines for animal research and received approval from the Institutional Animal Care and Use Committee at the Second Xiangya Hospital of Central South University (approval No. 20223872).

Conflict-of-interest statement: The authors declare that they have no conflict of interest.

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 are available from the corresponding author for legitimate inquiries.

Corresponding author: Xu-Yang Hou, MD, Doctor, Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha 410011, Hunan Province, China. houxuyang@csu.edu.cn

Received: January 12, 2026
Revised: March 9, 2026
Accepted: April 3, 2026
Published online: October 14, 2026
Processing time: 236 Days and 14.3 Hours

Abstract

BACKGROUND

Severe acute pancreatitis (SAP) is characterized by inflammatory injury and organ dysfunction, yet the contribution of macrophage extracellular traps (METs) to SAP pathogenesis is not fully understood.

AIM

To clarify METs involvement in the pathogenesis of SAP, as well as to investigate and evaluate the potential therapeutic effects of factors regulating MET formation in mitigating disease severity.

METHODS

In this study, SAP was induced in mice via duct ligation and caerulein injection, and MET formation was evaluated by measuring double-stranded DNA and citrullinated histone H3 expression. Interventions involving with deoxyribonuclease I (DNase I), a peptidylarginine deiminase 4 (PAD4) inhibitor, N-acetylcysteine, zinc supplementation, and ZIP8 overexpression were used to assess the effects of these treatments on METs and disease severity.

RESULTS

MET formation, which is dependent on the PAD4 and reactive oxygen species pathways, was significantly increased in SAP mice, mainly in M1 macrophages. Zinc supplementation and ZIP8 overexpression suppressed MET formation, restored zinc homeostasis, and reduced pancreatic and pulmonary injury, whereas DNase I exacerbated intestinal barrier dysfunction.

CONCLUSION

These findings indicate that targeting METs through zinc supplementation or ZIP8 could be a promising strategy for SAP treatment, underscoring the importance of zinc homeostasis in inflammatory disorders.

Keywords: Macrophage extracellular traps; Severe acute pancreatitis; Specificity protein 1; ZIP8; Zinc

Core Tip: This study reveals that severe acute pancreatitis triggers macrophage extracellular trap (MET) formation in M1 macrophages through peptidylarginine deiminase 4 and reactive oxygen species pathways, linked to zinc deficiency and ZIP expression downregulation. Zinc supplementation and ZIP8 overexpression mitigate MET formation and organ injury. Additionally, specificity protein 1’s role in regulating ZIP8 expression is highlighted, with its downregulation exacerbating zinc deficiency and MET formation, offering novel insights into therapeutic strategies.