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<p>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 <i>Galr2</i>-deficient mice, highlighting receptor dependency. Moreover, epithelial cell-specific <i>Arrb2</i> and <i>Gnaq</i> knockout models demonstrate that cGAL53 protects the gut barrier and reduces inflammation&#xa0;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.</p>

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A novel long-galanin peptide from non-mammalian vertebrates mitigates the inflammatory response in IBD models via the biased GALR2/β-arrestin2 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月13日

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  • 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

摘要

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.