Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 54 min ago
Peer-reviewedCC BY-NC 4.0Zoological Research

Spexin-GALR2-Gq axis as a biased signaling pathway for colitis therapy

  • Jing-Wen Xue1,2,3
  • Ting Zhang1,2,3
  • Xiang-Lin Kong4
  • Kun Zheng1,2,3
  • Yu-Wei Chen4
  • Kai-Li Ma4
  • Tao Zeng1,2,3
  • Juergen Brosius1
  • Fei Xu5
  • Shan-Shan Lai4
  • Cheng Deng1,2,3
5 affiliations
  1. 1Department of High Altitude Medicine, Center for High Altitude Medicine, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
  2. 2Institute of High Altitude Medicine, High Altitude Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
  3. 3Center for High Altitude Medicine, Xining, Qinghai 810000, China
  4. 4Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu 210023, China
  5. 5iHuman Institute, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Read full textPDFDOICite

Abstract

Inflammatory bowel disease (IBD) remains a major clinical challenge worldwide. Spexin (SPX), a neuropeptide that signals through galanin receptors (GALR2/3), has been implicated in metabolic and behavioral regulation. Here, we report that SPX effectively alleviates colitis, primarily by suppressing inflammation and promoting intestinal epithelial repair, outperforming its relative peptide, galanin (GAL). Mechanistically, SPX exhibits G protein-biased agonism at GALR2, whereas GAL favors β-arrestin2 recruitment. Utilizing Galr2-/- and Galr3-/- mice, receptor-specific inhibitors, and intestinal epithelial-specific Gnaq and Arrb2 knockout mice, we establish that the SPX-GALR2-Gq axis drives the protective effects of SPX in colitis. Structure-guided mutagenesis further pinpointed key residues governing this signaling bias and enabled the design of SPX p.Lys11Leu, a high-affinity GALR2 agonist that exerts potent anti-colitis activity at significantly lower doses than wild-type SPX. Collectively, our work defines the SPX-GALR2-Gq axis as a therapeutically relevant biased signaling pathway for colitis, and nominates SPX, particularly its p.Lys11Leu mutant, as a promising peptide drug candidate for IBD.

Related

  1. PPARγ signaling pathway: strategies and limitations of natural compounds in the treatment of ulcerative colitis
    Licheng Liang, Hualiang Deng
    Frontiers in PharmacologyPeer-reviewedCC BY 4.0Full textGenetics & genomicsCrossrefEurope PMCPMC
  2. Female-Biased IL-17/STAT3 Signaling Marks Dementia-Associated Microglial Inflammation in Alzheimer's Disease
    N. H. Abdelfattah, R. Kang, D. Jimenez +5
    bioRxivPreprintCC BY-NC-NDFull textNeurosciencebioRxiv
  3. Senkyunolide I Inhibits mtDNA‐cGAS‐STING Signaling in Macrophages via Targeting VDAC1 Oligomerization to Attenuate Ulcerative Colitis
    Zhiming Ye, Yihang Huang, Bohao Han +7
    Advanced SciencePeer-reviewedCC BY 4.0Full textImmunologyPMC
  4. Rhoifolin Alleviates Ulcerative Colitis by Targeting NMNAT1 and Activating SIRT1‐FOXO1 Signaling to Enhance ILC3s Effector Function
    Hongqiong Yang, Yishu Zhang, Sijia Feng +10
    Advanced SciencePeer-reviewedCC BY 4.0Full textGenetics & genomicsPMC
  5. Evaluating Upadacitinib in the Treatment of Moderate-to-Severe Active Ulcerative Colitis: Design, Development, and Potential Position in Therapy
    Maria Napolitano, Ferdinando d'Amico, Elisa Ragaini +2
    Drug Design, Development and TherapyPeer-reviewedCC BY-NC 4.0Full text30 citedGenetics & genomicsHAL

Cite

BibTeXRIS
BibTeX
@article{xue2026spexingalr2gq,
  title = {{Spexin-GALR2-Gq axis as a biased signaling pathway for colitis therapy}},
  author = {Jing-Wen Xue and Ting Zhang and Xiang-Lin Kong and Kun Zheng and Yu-Wei Chen and Kai-Li Ma and Tao Zeng and Juergen Brosius and Fei Xu and Shan-Shan Lai and Cheng Deng},
  journal = {Zoological Research},
  year = {2026},
  month = sep,
  doi = {10.24272/j.issn.2095-8137.2025.489},
  url = {https://doi.org/10.24272/j.issn.2095-8137.2025.489},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Spexin-GALR2-Gq axis as a biased signaling pathway for colitis therapy
AU  - Jing-Wen Xue
AU  - Ting Zhang
AU  - Xiang-Lin Kong
AU  - Kun Zheng
AU  - Yu-Wei Chen
AU  - Kai-Li Ma
AU  - Tao Zeng
AU  - Juergen Brosius
AU  - Fei Xu
AU  - Shan-Shan Lai
AU  - Cheng Deng
PY  - 2026
DA  - 2026/09/18
JO  - Zoological Research
DO  - 10.24272/j.issn.2095-8137.2025.489
UR  - https://doi.org/10.24272/j.issn.2095-8137.2025.489
AB  - Inflammatory bowel disease (IBD) remains a major clinical challenge worldwide. Spexin (SPX), a neuropeptide that signals through galanin receptors (GALR2/3), has been implicated in metabolic and behavioral regulation. Here, we report that SPX effectively alleviates colitis, primarily by suppressing inflammation and promoting intestinal epithelial repair, outperforming its relative peptide, galanin (GAL). Mechanistically, SPX exhibits G protein-biased agonism at GALR2, whereas GAL favors β-arrestin2 recruitment. Utilizing Galr2-/- and Galr3-/- mice, receptor-specific inhibitors, and intestinal epithelial-specific Gnaq and Arrb2 knockout mice, we establish that the SPX-GALR2-Gq axis drives the protective effects of SPX in colitis. Structure-guided mutagenesis further pinpointed key residues governing this signaling bias and enabled the design of SPX p.Lys11Leu, a high-affinity GALR2 agonist that exerts potent anti-colitis activity at significantly lower doses than wild-type SPX. Collectively, our work defines the SPX-GALR2-Gq axis as a therapeutically relevant biased signaling pathway for colitis, and nominates SPX, particularly its p.Lys11Leu mutant, as a promising peptide drug candidate for IBD.
SN  - 2095-8137
ER  -