Xinyue Lan, Qiu Dai, Yanhui Wang, Jiaxuan Gu, Chengyun Wang, Weicheng Xu, Xinru Gao, Jiageng Cheng, Wentao Geng, Xiaowen Wu, Haihang Li, Xiaoyun He, Shengwei Fu, Longjiao Zhu, Wentao Xu
Ethanol-induced acute gastric mucosal injury (AGMI) remains a prevalent clinical problem, while current therapies are constrained by adverse effects and the immunogenicity of animal-derived collagens. 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-fold greater protection than commercial animal-derived collagens, and exhibited excellent biosafety. Integrated metabolomic and transcriptomic analyses revealed coordinated regulation of glutathione-centered redox homeostasis, cytoskeletal and tight-junction barrier repair, and metabolic-inflammatory networks. Targeted LC-MS/MS confirmed the transient occurrence of the RC-derived pentapeptide GPAEF in gastric mucosal lavage 30 min after administration. GPAEF selectively recognized and stabilized the Pla2g4a promoter G-quadruplex (G4), exhibiting approximately 13-fold 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-G4 complex, providing a dynamic basis for Pla2g4a transcription and downstream prostaglandin biosynthesis. These findings establish RC as a safe and effective biomaterial for ethanol-associated gastropathy and identify G4-mediated activation of the Pla2g4a-prostaglandin axis as a key pathway contributing to its gastroprotective effects.