Abstract
Galanin, a neuropeptide, regulates immune and inflammatory responses via GALR1-3. GALRs have emerged as potential therapeutic targets for inflammatory bowel disease (IBD), yet their mechanistic roles remain unclear. Based on evolutionary analysis, we identified a long galanin isoform (GAL53), generated by alternative splicing in non-mammalian vertebrates. Here we show that the chicken ortholog cGAL53 is robustly expressed in colonic tissue but downregulated upon dextran sulfate sodium (DSS)-induced colitis. Administration of cGAL53 alleviates colitis-associated weight loss, colon shortening, bleeding, and inflammation in both chickens and mice. These effects are abolished in Galr2-deficient mice, highlighting receptor dependency. Moreover, epithelial cell-specifi…
Abstract
Galanin, a neuropeptide, regulates immune and inflammatory responses via GALR1-3. GALRs have emerged as potential therapeutic targets for inflammatory bowel disease (IBD), yet their mechanistic roles remain unclear. Based on evolutionary analysis, we identified a long galanin isoform (GAL53), generated by alternative splicing in non-mammalian vertebrates. Here we show that the chicken ortholog cGAL53 is robustly expressed in colonic tissue but downregulated upon dextran sulfate sodium (DSS)-induced colitis. Administration of cGAL53 alleviates colitis-associated weight loss, colon shortening, bleeding, and inflammation in both chickens and mice. These effects are abolished in Galr2-deficient mice, highlighting receptor dependency. Moreover, epithelial cell-specific Arrb2 and Gnaq knockout models demonstrate that cGAL53 protects the gut barrier and reduces inflammation by activating β-arrestin2-biased GALR2 signaling. Our findings reveal a naturally occurring long galanin peptide with potent anti-inflammatory activity and propose evolutionary medicine-guided biased GALR2 agonism as a therapeutic strategy for IBD.
Data availability
Publicly available datasets and databases used were following: colon biopsies from IBD patients and healthy controls (GSE11223, GSE235236). The RNA-sequencing generated in this study have been deposited in the NCBI database under accession code ID [PRJNA1334145]. All other data are available within the paper and its supplementary information. This manuscript does not report original code. Source data are provided with this paper.
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Acknowledgements
This work was supported by National Natural Science Foundation of China (32170498 to S.S.L, 32270438 to C.D); National Science and Technology Major Project for Prevention and Treatment of Cancers, Cardio-cerebrovascular Diseases, Respiratory Diseases, and Metabolic Diseases (2025ZD0551800 to C.D); National Science and Technology Major Project (2023ZD0506800 to C.D); National Key R&D Program of China (2021YFF0702000 to C.D); 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYYC21011 to C.D); 1.3.5 Project of Center for High Altitude Medicine, West China Hospital, Sichuan University (GYYX24018 to C.D); National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z2023JC003 to C.D); Science and Technology Department of Sichuan Province (2022YFH0116 and TJZ2025EM08 to C.D); the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD to C.D); the “Kun lun Talents” of Qinghai-Top-Notch and Pioneering talent of Innovation and Entrepreneurship to C.D.
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Author notes
These authors contributed equally: Shanshan Lai, Xianglin Kong, Jingwen Xue, Kaili Ma, Amanullah Amanullah.
Authors and Affiliations
Jiangsu Key Laboratory for Biodiversity and Biotechnology, State Key Laboratory of Microbial Technology, College of Life Sciences, Nanjing Normal University, Nanjing, PR China
Shanshan Lai, Xianglin Kong, Kaili Ma, Amanullah Amanullah, Yuwei Chen, Na Yang, Ting Zhang, Xiaofei Yan, Shah Kamal & Najeeb Ullah 1.
Department of High Altitude Medicine, Center for High Altitude Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
Jingwen Xue, Kun Zheng, Tao Zeng, Chang Zhang, Juergen Brosius & Cheng Deng 1.
Institute of High Altitude Medicine, High Altitude Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
Jingwen Xue, Kun Zheng, Tao Zeng, Chang Zhang & Cheng Deng 1.
Department of Life Sciences, Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
Chingwei Luo 1.
Center for High Altitude Medicine, Xining, Qinghai, P. R. China
Cheng Deng
Authors
- Shanshan Lai
- Xianglin Kong
- Jingwen Xue
- Kaili Ma
- Amanullah Amanullah
- Yuwei Chen
- Na Yang
- Ting Zhang
- Kun Zheng
- Tao Zeng
- Xiaofei Yan
- Chang Zhang
- Shah Kamal
- Najeeb Ullah
- Chingwei Luo
- Juergen Brosius
- Cheng Deng
Contributions
C.D. and S.L. conceived and supervised the whole project; X.K., J.X., K.M., Y.C., X.Y., S.L., S.K., N.Y., T.Z., N.J., A.A., C.Z., N.U., and T.Z. conducted experiments; J.X., X.Y., and K.Z. performed the GEO data and RNA sequencing analysis; X.K., J.X., S.L., C.L., A.A., K.M., and C.D. performed data analysis and interpretation; S.L. and X.K. wrote the paper; J.B., S.L., and C.D. revised the paper.
Corresponding author
Correspondence to Cheng Deng.
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Lai, S., Kong, X., Xue, J. et al. A novel long-galanin peptide from non-mammalian vertebrates mitigates the inflammatory response in IBD models via the biased GALR2/β-arrestin2 pathway. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66335-1
Received: 01 January 2025
Accepted: 03 November 2025
Published: 13 December 2025
DOI: https://doi.org/10.1038/s41467-025-66335-1