Oral Recombinant Human Collagen III Protects Gastric Mucosa via G-Quadruplex-Mediated Activation of the Pla2g4a-Prostaglandin Axis.

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.