Xenin-Derived Peptides: Multifaceted Regulators and Therapeutic Innovations in Metabolic Diseases

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.