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Here, we evaluate orally administered recombinant human type III collagen (RC) as a gastroprotective biomaterial. Following oral administration, RC reduced gastric mucosal lesion area by 78% within the dynamic acidic gastric environment, provided approximately 1.5\u2010fold greater protection than commercial animal\u2010derived collagens, and exhibited excellent biosafety. Integrated metabolomic and transcriptomic analyses revealed coordinated regulation of glutathione\u2010centered redox homeostasis, cytoskeletal and tight\u2010junction barrier repair, and metabolic\u2010inflammatory networks. Targeted LC\u2010MS\/MS confirmed the transient occurrence of the RC\u2010derived pentapeptide GPAEF in gastric mucosal lavage 30 min after administration. GPAEF selectively recognized and stabilized the Pla2g4a promoter G\u2010quadruplex (G4), exhibiting approximately 13\u2010fold higher affinity than ThT and enhancing G4 folding under physiologically relevant ionic conditions. Molecular dynamics simulations indicated that GPAEF shifted the Pla2g4a G4 from a preferentially parallel topology toward hybrid\/mixed conformations and stabilized the peptide\u2010G4 complex, providing a dynamic basis for Pla2g4a transcription and downstream prostaglandin biosynthesis. These findings establish RC as a safe and effective biomaterial for ethanol\u2010associated gastropathy and identify G4\u2010mediated activation of the Pla2g4a\u2010prostaglandin axis as a key pathway contributing to its gastroprotective effects.<\/jats:p>","DOI":"10.1002\/advs.77964","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Oral Recombinant Human Collagen III Protects Gastric Mucosa via G\u2010Quadruplex\u2010Mediated Activation of the Pla2g4a\u2010Prostaglandin Axis"],"prefix":"10.1002","author":[{"given":"Xinyue","family":"Lan","sequence":"first","affiliation":[{"name":"Food Laboratory of Zhongyuan Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University  Beijing People's Republic of 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