Capsaicin suppresses microglial inflammation through TRPV1-SSR4 interaction.
9 affiliations
- 1School of Integrative Medicine and State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- 2Shuguang Lab of Future Health, Shanghai Frontiers Science Center of TCM Chemical Biology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
- 3State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Center for Clinical Neuro-AI, Institute for Translational Brain Research, Fudan University, Shanghai, China.
- 4State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Center for Clinical Neuro-AI, Institute for Translational Brain Research, Fudan University, Shanghai, China. [email protected].
- 5Department of Emergency Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
- 6School of Integrative Medicine and State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. [email protected].
- 7Shuguang Lab of Future Health, Shanghai Frontiers Science Center of TCM Chemical Biology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. [email protected].
- 8School of Integrative Medicine and State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. [email protected].
- 9Shuguang Lab of Future Health, Shanghai Frontiers Science Center of TCM Chemical Biology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China. [email protected].
Abstract
Background
Transient receptor potential vanilloid 1 (TRPV1) is increasingly recognized as an important regulator of microglial response during neuroinflammation, a key pathological feature of various neurodegenerative diseases such as Alzheimer's disease. Capsaicin, the primary pungent component in chili peppers, executes its anti-inflammatory properties as a TRPV1 agonist. Although the mechanism of TRPV1 channel activation and signal transduction by capsaicin has been extensively studied, the protein-protein interaction-based mechanisms by which TRPV1 modulates microglial inflammatory responses in the context of neurodegeneration remains unclear.Methods
We used a lipopolysaccharide-induced acute neuroinflammation model to examine the effects of TRPV1 activation and pharmacological blockade of TRPV1 channel gating on microglial inflammatory responses. Proximity labeling-based proteomics, bioluminescence resonance energy transfer, and NanoLuc Binary Technology were used to identify and characterize TRPV1-interacting proteins. Signal sequence receptor subunit 4 (SSR4) knockdown and forced interaction between TRPV1 and SSR4 were performed to assess the functional contribution of the TRPV1-SSR4 interaction. Structural modeling, BRET-based domain mapping, and colocalization analyses were further used to examine the molecular and subcellular features of SSR4 recruitment by TRPV1.Results
In the neuroinflammatory model, the TRPV1 agonist capsaicin attenuated pro-inflammatory cytokine production, neuronal apoptosis, microgliosis, and microglial soma enlargement in a TRPV1-dependent manner. Notably, pharmacological blockade of TRPV1 channel gating by capsazepine did not abolish the anti-inflammatory action of capsaicin, suggesting an alternative mechanism of action beyond the canonical ligand-gated Ca²⁺ influx. Screening of TRPV1 prey proteins and validation strategy identified SSR4 as a capsaicin-responsive, TRPV1-associated protein. SSR4 knockdown in microglia significantly diminished the suppression of inflammatory responses caused by TRPV1 activation. Conversely, forced interaction between TRPV1 and SSR4 partially mimicked the anti-inflammatory effects of TRPV1 activation. Further structural and cellular analyses suggested that the transmembrane region of TRPV1 supports SSR4 recruitment.Conclusions
Our findings suggest that capsaicin suppresses microglial inflammation mediated by the TRPV1-SSR4 interaction, providing new insights into the chemical biology basis of TRPV1 interoceptive signaling and potential applications of natural TRPV1 agonists for modifying therapy of neuroinflammation-associated neurodegeneration.
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BibTeX
@article{hou2026capsaicin,
title = {{Capsaicin suppresses microglial inflammation through TRPV1-SSR4 interaction.}},
author = {Yifei Hou and Sichen Wang and Yuzhang Yang and Zhenzhen Zhao and Yuanyuan Xie and Xiaoyan Ouyang and Kaihua Zhang and Hongzhuan Chen and Jianrong Xu},
journal = {Translational neurodegeneration},
year = {2026},
month = oct,
doi = {10.1186/s40035-026-00589-7},
url = {https://europepmc.org/article/MED/42902421},
note = {CC BY},
}
RIS
TY - JOUR
TI - Capsaicin suppresses microglial inflammation through TRPV1-SSR4 interaction.
AU - Yifei Hou
AU - Sichen Wang
AU - Yuzhang Yang
AU - Zhenzhen Zhao
AU - Yuanyuan Xie
AU - Xiaoyan Ouyang
AU - Kaihua Zhang
AU - Hongzhuan Chen
AU - Jianrong Xu
PY - 2026
DA - 2026/10/21
JO - Translational neurodegeneration
DO - 10.1186/s40035-026-00589-7
UR - https://europepmc.org/article/MED/42902421
AB - Background Transient receptor potential vanilloid 1 (TRPV1) is increasingly recognized as an important regulator of microglial response during neuroinflammation, a key pathological feature of various neurodegenerative diseases such as Alzheimer's disease. Capsaicin, the primary pungent component in chili peppers, executes its anti-inflammatory properties as a TRPV1 agonist. Although the mechanism of TRPV1 channel activation and signal transduction by capsaicin has been extensively studied, the protein-protein interaction-based mechanisms by which TRPV1 modulates microglial inflammatory responses in the context of neurodegeneration remains unclear.Methods We used a lipopolysaccharide-induced acute neuroinflammation model to examine the effects of TRPV1 activation and pharmacological blockade of TRPV1 channel gating on microglial inflammatory responses. Proximity labeling-based proteomics, bioluminescence resonance energy transfer, and NanoLuc Binary Technology were used to identify and characterize TRPV1-interacting proteins. Signal sequence receptor subunit 4 (SSR4) knockdown and forced interaction between TRPV1 and SSR4 were performed to assess the functional contribution of the TRPV1-SSR4 interaction. Structural modeling, BRET-based domain mapping, and colocalization analyses were further used to examine the molecular and subcellular features of SSR4 recruitment by TRPV1.Results In the neuroinflammatory model, the TRPV1 agonist capsaicin attenuated pro-inflammatory cytokine production, neuronal apoptosis, microgliosis, and microglial soma enlargement in a TRPV1-dependent manner. Notably, pharmacological blockade of TRPV1 channel gating by capsazepine did not abolish the anti-inflammatory action of capsaicin, suggesting an alternative mechanism of action beyond the canonical ligand-gated Ca²⁺ influx. Screening of TRPV1 prey proteins and validation strategy identified SSR4 as a capsaicin-responsive, TRPV1-associated protein. SSR4 knockdown in microglia significantly diminished the suppression of inflammatory responses caused by TRPV1 activation. Conversely, forced interaction between TRPV1 and SSR4 partially mimicked the anti-inflammatory effects of TRPV1 activation. Further structural and cellular analyses suggested that the transmembrane region of TRPV1 supports SSR4 recruitment.Conclusions Our findings suggest that capsaicin suppresses microglial inflammation mediated by the TRPV1-SSR4 interaction, providing new insights into the chemical biology basis of TRPV1 interoceptive signaling and potential applications of natural TRPV1 agonists for modifying therapy of neuroinflammation-associated neurodegeneration.
SN - 2047-9158
ER -