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已发表论文
源自外泌体的肽：代谢性疾病中的多面调节剂与治疗创新
Authors Gong B, Liu X , Hu G, Li T, Chen F, Sun X, Sun L, Xu Y
Received 3 September 2025
Accepted for publication 18 December 2025
Published 27 December 2025 Volume 2025:19 Pages 11799—11815
DOI https://doi.org/10.2147/DDDT.S565077
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Tuo Deng
Binbin Gong,1,2,* Xiyu Liu,1,2,* Guoqiang Hu,1 Tongtong Li,2 Fei Chen,2 Xueqing Sun,2 Lidan Sun,1,2 Yinghe Xu1
1Taizhou Hospital, Zhejiang University, Taizhou, 317000, People’s Republic of China; 2College of Medicine, Jiaxing University, Jiaxing, 314001, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Lidan Sun; Yinghe Xu, Taizhou Hospital, Zhejiang University, Taizhou, 317000, People’s Republic of China, Tel +86-18358328736, Fax +86-573-83643848, Email slidan89@zjxu.edu.cn; xuyh@enzemed.com
Abstract: Xenin, a 25-amino acid peptide hormone predominantly secreted by intestinal K cells, demonstrates evolutionary conservation with neuropeptides such as xenopsin and neurotensin. Functionally, it engages neurotensin receptor 1 (NTSR1) to regulate appetite via hypothalamic signaling pathways and modulates glucose homeostasis through synergistic interactions with incretin hormones. Preclinical studies highlight its dual role in suppressing appetite and enhancing pancreatic β-cell survival, while a single pilot human study suggests xenin-25 may delay gastric emptying and attenuate postprandial glucose excursions; however, these data await independent confirmation. Native xenin, however, is constrained by rapid proteolytic degradation and limited bioavailability. Advances in peptide engineering, including C-terminal truncation, site-directed amino acid substitution, and lipidation, have generated analogues that exhibit prolonged metabolic activity in rodent models, with plasma half-life extended from minutes to hours. In murine models of metabolic dysfunction, these derivatives enhance insulin secretion, improve glycaemic profiles and restore incretin responsiveness. Furthermore, multi-agonist peptides combining xenin with other gastrointestinal hormones show synergistic potential in preclinical studies, concurrently augmenting insulin secretion and reducing energy intake, though their clinical relevance remains to be validated in human trials. Despite promising preclinical outcomes, challenges persist in translating xenin-based therapies to clinical practice, including incomplete mechanistic insights into receptor cross-talk and species-specific variations in gastrointestinal responses. This review uniquely integrates the preclinical landscape of xenin biology, peptide-engineering principles, and emerging multi-agonist design, identifying knowledge gaps critical for future translation. We conclude that xenin-based therapeutics are a promising yet early-stage strategy whose efficacy and safety in human metabolic diseases remain to be established through rigorous pharmacokinetic profiling and phased clinical trials.
keywords: Xenin, type 2 diabetes, obesity, physiological function, structural modification
1Taizhou Hospital, Zhejiang University, Taizhou, 317000, People’s Republic of China; 2College of Medicine, Jiaxing University, Jiaxing, 314001, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Lidan Sun; Yinghe Xu, Taizhou Hospital, Zhejiang University, Taizhou, 317000, People’s Republic of China, Tel +86-18358328736, Fax +86-573-83643848, Email slidan89@zjxu.edu.cn; xuyh@enzemed.com
Abstract: Xenin, a 25-amino acid peptide hormone predominantly secreted by intestinal K cells, demonstrates evolutionary conservation with neuropeptides such as xenopsin and neurotensin. Functionally, it engages neurotensin receptor 1 (NTSR1) to regulate appetite via hypothalamic signaling pathways and modulates glucose homeostasis through synergistic interactions with incretin hormones. Preclinical studies highlight its dual role in suppressing appetite and enhancing pancreatic β-cell survival, while a single pilot human study suggests xenin-25 may delay gastric emptying and attenuate postprandial glucose excursions; however, these data await independent confirmation. Native xenin, however, is constrained by rapid proteolytic degradation and limited bioavailability. Advances in peptide engineering, including C-terminal truncation, site-directed amino acid substitution, and lipidation, have generated analogues that exhibit prolonged metabolic activity in rodent models, with plasma half-life extended from minutes to hours. In murine models of metabolic dysfunction, these derivatives enhance insulin secretion, improve glycaemic profiles and restore incretin responsiveness. Furthermore, multi-agonist peptides combining xenin with other gastrointestinal hormones show synergistic potential in preclinical studies, concurrently augmenting insulin secretion and reducing energy intake, though their clinical relevance remains to be validated in human trials. Despite promising preclinical outcomes, challenges persist in translating xenin-based therapies to clinical practice, including incomplete mechanistic insights into receptor cross-talk and species-specific variations in gastrointestinal responses. This review uniquely integrates the preclinical landscape of xenin biology, peptide-engineering principles, and emerging multi-agonist design, identifying knowledge gaps critical for future translation. We conclude that xenin-based therapeutics are a promising yet early-stage strategy whose efficacy and safety in human metabolic diseases remain to be established through rigorous pharmacokinetic profiling and phased clinical trials.
keywords: Xenin, type 2 diabetes, obesity, physiological function, structural modification