Background <p>Proton pump inhibitors are the standard treatment for peptic ulcers, but their incomplete curative effect, potential long-term adverse effects, and high cost have spurred interest in natural alternatives. Collagen sourced from farmed tilapia and other marine organisms is emerging as a safe, effective option in biomedical research while mitigating the environmental and economic burden of fish-waste disposal. In particular, collagen derived from tilapia skin shows promise as a natural therapeutic for managing gastric ulcers.</p> Purpose <p>Examining the gastroprotective properties of collagen extracted from tilapia skin and /or vitamin C against gastric ulcer due to acute exposure to Ethanol (5 ml/kg).</p> Methods <p>Fifty rats were randomly divided into 10 equal groups (n =5 rats). Group 1, a normal control group. Group 2, received Omeprazole (20 mg/kg, orally) (a standard anti-ulcer drug). Groups 3, 4 and 5 were treated with vitamin C (40mg/kg orally), Tilapia collagen (4g/kg orally), Tilapia collagen and vitamin C respectively daily for 1 week (3 days/week). Group 6 (gastritis non-treated group) was administered with a single oral dose of absolute ethanol and kept as a control positive group. Groups 7, 8, 9, and 10 treated by Omeprazole drug, vitamin C, tilapia collagen and tilapia collagen and vitamin C respectively for 1 week then administered a single oral dose of absolute ethanol after 24 hours fasting. Stomach samples were collected for gene expression analysis, light microscope, and transmission electron microscope examination.</p> Results <p>Gastric ulceritis induced by absolute ethanol was associated with down regulation of Sod, Gpx, Il10 and Bcl-2 and upregulation of Nfkb, Tnfα, Smad7 and Bax. Light microscopy revealed acute to subacute gastritis, characterized by erosion of gastric mucosal epithelium, hyperemia in submucosal blood vessels, necrosis of gastric glands, and the presence of lymphocytes and neutrophils within the submucosa of the gastric tissue. TEM examination demonstrated extensive damage of gastric epithelial cells with either reduction in nuclear size or complete loss of nucleus, dilation and distortion of cytoplasmic organelles, rupture and damage of epithelial cell membrane with loss of tight junction between gastric epithelial cells with either separation of cells or complete fragmented cells. Pretreatment of tilapia collagen and/or vitamin C was able to reverse the aforementioned findings.</p> Conclusion <p>Tilapia collagen and/or vitamin C could alleviate ethanol-induced gastric ulcer through modulating anti-inflammatory and anti-oxidant status and anti-apoptotic mechanisms</p> Graphical Abstract <p></p>