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Interaction between transient receptor potential vanilloid 4 and glutamate NMDA receptor subunit 1 mediates endoplasmic reticulum stress and neuroinflammation in postoperative delirium.

Overview

Authors: Shiqian Huang1,2,3, Tianhao Zhang1,2,3, Yu Wang1,2,3, Hongying Du4, Jingang He5, Hongchun Zeng6, Lulin Ma1,2,3, Daling Deng1,2,3, Yuxi Zhou1,2,3, Shiya Liu1,2,3, Wenjing Zhao1,2,3, Xinxin Yang1,2,3, Linlin Han1,2,3, Shuai Zhao7, Shaofang Shu1,2,3, Shanglong Yao1,2,3, Qi Zhong2,7, Xiangdong Chen1,2,3, Jie Wang6
ORCID iDs: Qi Zhong, Xiangdong Chen, Jie Wang
  1. Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 P. R. China
  2. Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, 430022 P. R. China
  3. Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 P. R. China
  4. College of Light Industry and Food Engineering, Nanjing Forestry University, Nanjing, Jiangsu Province 210037 P. R. China
  5. University of Chinese Academy of Sciences, Beijing, P. R. China
  6. Department of Utrasonography, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders (LEAD), Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China
  7. Department of Anesthesiology, Zhongnan Hospital, Wuhan University, East Lake Road, Wuhan, 430071 P. R. China
Institutions: Wuhan Union Hospital (China); Huazhong University of Science and Technology (China); Nanjing Forestry University (China); University of Chinese Academy of Sciences (China); Shanghai Jiao Tong University (China); Wuhan University (China); Zhongnan Hospital of Wuhan University (China)
Journal: Molecular biomedicine, volume 7, issue 1, article 22
Dates: received 1 August 2025; accepted 24 February 2026; published online 7 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1186/s43556-026-00421-8 · PMID 41792369 · PMCID PMC12965926 · OpenAlex W7134129771
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: human (organism), mouse (organism), other condition (population), cellular / molecular (subfield)
Methods: Statistics, Machine learning
Keywords: Postoperative delirium, TRPV4, GluN1, Endoplasmic reticulum stress, Neuroinflammation
MeSH: Delirium*, Endoplasmic Reticulum Stress*, Nerve Tissue Proteins*, Neuroinflammatory Diseases*, Postoperative Complications*, Receptors, N-Methyl-D-Aspartate*, TRPV Cation Channels*, Animals, Disease Models, Animal, Hippocampus, Humans, Male, Mice, Mice, Inbred C57BL, Neurons, Signal Transduction (* major topic)
Topic: Intensive Care Unit Cognitive Disorders (Critical Care and Intensive Care Medicine, Medicine), according to OpenAlex
Funding: National Natural Science Foundation of China (82401847, 32271148, 82471251, 82471504, 82201350); Research Grant of Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education (2024MZFS002); Biosecurity Research Project (23SWAQ24)
Citations: cited by 1 paper (Europe PMC); 41 references in the paper

Abstract

Postoperative delirium (POD) is a serious and prevalent neurocognitive complication that poses a major clinical challenge because its mechanism is unclear. This study identifies a pathogenic pathway centred on the direct interaction between transient receptor potential vanilloid 4 (TRPV4) and the essential N-methyl-D-aspartate receptor (NMDAR) subunit GluN1. Using a murine POD model, the neuron-centric glutamatergic dysfunction in the hippocampus was initially confirmed through ex vivo metabolic kinetic analysis. Transcriptomic analysis revealed upregulation of Trpv4, predominantly in neurons. Co-immunoprecipitation coupled with mass spectrometry revealed that TRPV4 directly interacts with GluN1. This enhanced TRPV4-GluN1 coupling promoted GluN1 phosphorylation at serine 896 and hyperactivated NMDAR signalling. We subsequently observed the concurrent induction of endoplasmic reticulum (ER) stress, as evidenced by a dilated ER ultrastructure and the upregulation of the expression of UPR markers (ATF6, p-PERK, p-IRE1α, and CHOP), as well as neuroinflammation, characterized by microglial activation and elevated expression of proinflammatory mediators (IL-6, IL-1β, and ICAM-1). These molecular pathologies were associated with decreased neuronal activity and the characteristic cognitive-affective deficits associated with POD. Critically, both pharmacological inhibition of TRPV4 (HC067047) and hippocampal CA3-specific Trpv4 knockdown reversed these pathologies and rescued the behaviour. Inhibiting NMDAR with MK801 recapitulated these therapeutic benefits. Furthermore, TRPV4 was significantly upregulated in early-onset Alzheimer’s disease patients. Our study defines a novel TRPV4-GluN1 axis that drives POD pathogenesis, suggesting that it is a promising therapeutic target.

Supplementary Information: The online version contains supplementary material available at 10.1186/s43556-026-00421-8.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

Data availability

The RNA-seq data reported in this paper have been deposited in the OMIX, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (https://ngdc.cncb.ac.cn/omix: accession no. OMIX015110). All other data supporting the findings of this study are available from the corresponding author, Jie Wang, upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 19 authors, 5 keywords, 16 MeSH terms, 3 funders, 41 references.

Cite

This paper

Huang, S., Zhang, T., Wang, Y., Du, H., He, J., Zeng, H., Ma, L., Deng, D., Zhou, Y., Liu, S., Zhao, W., Yang, X., Han, L., Zhao, S., Shu, S., Yao, S., Zhong, Q., Chen, X., & Wang, J. (2026). Interaction between transient receptor potential vanilloid 4 and glutamate NMDA receptor subunit 1 mediates endoplasmic reticulum stress and neuroinflammation in postoperative delirium. Molecular biomedicine, 7(1), 22. https://doi.org/10.1186/s43556-026-00421-8

BibTeX

@article{huang2026interaction,
author = {Huang, Shiqian and Zhang, Tianhao and Wang, Yu and Du, Hongying and He, Jingang and Zeng, Hongchun and Ma, Lulin and Deng, Daling and Zhou, Yuxi and Liu, Shiya and Zhao, Wenjing and Yang, Xinxin and Han, Linlin and Zhao, Shuai and Shu, Shaofang and Yao, Shanglong and Zhong, Qi and Chen, Xiangdong and Wang, Jie},
title = {{Interaction between transient receptor potential vanilloid 4 and glutamate NMDA receptor subunit 1 mediates endoplasmic reticulum stress and neuroinflammation in postoperative delirium}},
journal = {Molecular biomedicine},
year = {2026},
month = mar,
volume = {7},
number = {1},
pages = {22},
publisher = {Springer},
issn = {2662-8651},
doi = {10.1186/s43556-026-00421-8},
url = {https://doi.org/10.1186/s43556-026-00421-8},
pmid = {41792369},
pmcid = {PMC12965926}
}

RIS

TY - JOUR
AU - Huang, Shiqian
AU - Zhang, Tianhao
AU - Wang, Yu
AU - Du, Hongying
AU - He, Jingang
AU - Zeng, Hongchun
AU - Ma, Lulin
AU - Deng, Daling
AU - Zhou, Yuxi
AU - Liu, Shiya
AU - Zhao, Wenjing
AU - Yang, Xinxin
AU - Han, Linlin
AU - Zhao, Shuai
AU - Shu, Shaofang
AU - Yao, Shanglong
AU - Zhong, Qi
AU - Chen, Xiangdong
AU - Wang, Jie
TI - Interaction between transient receptor potential vanilloid 4 and glutamate NMDA receptor subunit 1 mediates endoplasmic reticulum stress and neuroinflammation in postoperative delirium
T2 - Molecular biomedicine
J2 - Mol Biomed
PY - 2026
DA - 2026/03/07
VL - 7
IS - 1
SP - 22
SN - 2662-8651
PB - Springer
DO - 10.1186/s43556-026-00421-8
UR - https://doi.org/10.1186/s43556-026-00421-8
LA - en
ER -

CSL-JSON

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