Esmolol alleviates lipopolysaccharide-induced intestinal injuries by enhancing autophagy through the AMPK/mTOR/ULK1 pathway

doi:10.3748/wjg.v32.i23.117320

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Publication Name

World Journal of Gastroenterology

ISSN

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. Jun 21, 2026; 32(23): 117320
Published online Jun 21, 2026. doi: 10.3748/wjg.v32.i23.117320

Esmolol alleviates lipopolysaccharide-induced intestinal injuries by enhancing autophagy through the AMPK/mTOR/ULK1 pathway

Yan-Bing Zhang, Zhe-Jun Yu, Jun Jin, Mao-Xia Liu, Fu-Hai Ji, Xin-Jing Yang

Yan-Bing Zhang, Fu-Hai Ji, Department of Anesthesiology and Pain Management, The First Affiliated Hospital, Soochow University, Suzhou 215006, Jiangsu Province, China

Zhe-Jun Yu, Jun Jin, Mao-Xia Liu, Xin-Jing Yang, Department of Intensive Care Unit, The First Affiliated Hospital, Soochow University, Suzhou 215006, Jiangsu Province, China

Co-corresponding authors: Fu-Hai Ji and Xin-Jing Yang.

Author contributions: Zhang YB and Yang XJ designed and performed most of the investigation; Yu ZJ analyzed the data and Zhang YB wrote the original draft manuscript; Jin J and Liu MX contributed to interpretation of the data and analyses; Ji FH and Yang XJ contributed to revising the article and modifying the figures. All authors have read and approved the manuscript. We propose the designation of two co-corresponding authors to formally acknowledge their shared, equal responsibility for the scientific integrity, methodological rigor, and long-term reproducibility of this fully experimental study. Ji FH conceived the study, led the overall experimental design, secured funding, coordinated cross-functional resources and team execution, oversaw regulatory compliance and administrative approvals, and provided substantive guidance throughout manuscript drafting and revision. Yang XJ led the development and implementation of the experimental methodology-including protocol design, assay optimization, data workflow architecture, analytical robustness validation, data curation, and establishment of an end-to-end reproducibility framework (encompassing version-controlled datasets, comprehensive documentation, and auditable provenance trails). Correspondence regarding conceptual rationale, study interpretation, and editorial or reader inquiries will be jointly managed. Ji FH serves as the primary contact for questions related to study design, strategic oversight, and high-level scientific direction; Yang XJ serves as the primary contact for technical implementation, methodological details, data access, and reproducibility infrastructure. This co-corresponding authorship arrangement ensures authoritative, timely, and coordinated responses; maintains continuity across the research lifecycle; strengthens transparency; and accurately reflects their equivalent accountability for the validity, reliability, and enduring utility of the work.

Supported by National Natural Science Foundation of China, No. 82471281; Key Medical Research Projects in Jiangsu Province, No. ZD2022021; and Key R&D Program Projects in Jiangsu Province, No. BE2023709.

Institutional review board statement: This study does not involve any human experiments.

Institutional animal care and use committee statement: All animal procedures were approved by the Medical Ethics Committee of The First Affiliated Hospital of Soochow University with the Public Health Service Policy on Humane Care and Use of Laboratory Animals. All methods were conducted in accordance with relevant guidelines and regulations. All methods were reported in accordance with ARRIVE guidelines.

Conflict-of-interest statement: No conflict of interests.

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: Data are ethically restricted, and they cannot be shared publicly. Data are available from the corresponding author by request subject to ethical considerations.

Corresponding author: Xin-Jing Yang, MD, Department of Intensive Care Unit, The First Affiliated Hospital, Soochow University, No. 188 Shi-Zi Road, Suzhou 215006, Jiangsu Province, China. yangxinjingsuda@163.com

Received: December 5, 2025
Revised: February 5, 2026
Accepted: March 12, 2026
Published online: June 21, 2026
Processing time: 185 Days and 17.6 Hours

Abstract

BACKGROUND

Beta-1 receptor blockade is well characterized for its protective effects against septic symptoms, and esmolol (ES) is a selective β1-adrenoceptor antagonist.

AIM

To assess the effects of ES on lipopolysaccharide (LPS)-induced septic intestinal damage and explore the associated mechanism by focusing on the AMPK/mTOR/ULK1 pathway.

METHODS

Sepsis was induced via an intraperitoneal injection of LPS in male SD rats or LPS treatment in rat intestine epithelial cells. To assess their anti-sepsis effects, rats and cells were pretreated with ES, 3-methyladenine, rapamycin (RAPA), and/or compound C, 30 minutes before LPS exposure. Then, intestinal damage, intestinal fatty acid-binding protein (I-FABP) and diamine oxidase (DAO) levels in intestinal tissue, interleukin (IL)-6, IL-1, tumor necrosis factor-α (TNF-α), IL-17, and IL-10 levels, cell viability, autophagic processes, and AMPK/mTOR/ULK1-related signaling transduction were detected via a series of in vivo and in vitro assays.

RESULTS

LPS induced intestinal damage in a time-dependent manner and suppressed autophagy at 12 and 24 hours. Pretreatment with ES or RAPA reduced I-FABP and DAO release; improved the damage score; and increased the expression of Beclin-1, LC3-II, p-AMPK, p-ULK1 and numbers of autophagosomes, and decreased the expression of p-mTOR at 12 and 24 hours, indicating amelioration of intestinal injury and augmentation of autophagy in rats. The results of in vivo assays were consistent with those in the IEC-6 intestinal epithelial cell line. Pre-treatment with ES reduced IL-1, TNF-α, IL-17, and IL-6 release and increased IL-10 release in cells.

CONCLUSION

The current findings demonstrate that ES ameliorates LPS-induced septic intestinal damage by activating autophagy through modulation of the AMPK/mTOR/ULK1 pathway.

Keywords: Esmolol; AMPK/mTOR/ULK1; Autophagy; Sepsis; Intestinal injury; Lipopolysaccharide

Core Tip: This study investigated the protective effects of esmolol (ES), a selective β1-blocker, against lipopolysaccharide-induced septic intestinal damage. Using both animal and cell models, researchers found that ES pretreatment reduced intestinal injury markers (intestinal fatty acid-binding protein and diamine oxidase), improved tissue damage scores, and suppressed inflammation by suppressing interleukin (IL)-1 tumor necrosis factor-α, IL-17, and IL-6 while enhancing IL-10. Mechanistically, ES enhanced autophagy through activation of the AMPK/mTOR/ULK1 signaling pathway, as shown by increasing the expression of Beclin-1, LC3-II, p-AMPK, p-ULK1 and numbers of autophagosomes, and decreasing the expression of p-mTOR. These effects were consistent in both in vivo and in vitro models. The findings suggest that ES alleviates septic intestinal injury by promoting autophagy via the AMPK/mTOR/ULK1 pathway.