Gastric Ulcer Disease: A Comprehensive Review of Molecular Pathogenesis and Emerging Therapeutic Strategies

Abstract

Gastric ulcer disease is still a major cause of morbidity worldwide, despite substantial advances in acidsuppressive pharmacotherapy and declining rates of Helicobacter pylori infection in many regions. The 
disease is caused by disruption of the physiological equilibrium between aggressive luminal factors—
gastric acid, pepsin, Helicobacter pylori virulence determinants, and nonsteroidal anti-inflammatory 
drugs (NSAIDs)—and the mucosal defense mechanisms that maintain epithelial integrity, including 
mucus-bicarbonate secretion, prostaglandin synthesis, mucosal blood flow, and epithelial restitution. This 
review summarizes the current knowledge of the molecular pathways leading to gastric ulcerogenesis 
with particular emphasis on the Helicobacter pylori CagA/VacA-mediated epithelial injury, cyclooxygenase 
inhibition and prostaglandin depletion in NSAID-associated ulcers, oxidative and nitrosative stress, and 
the convergent activation of NF-κB, mitogen-activated protein kinase and NLRP3 inflammasome signaling 
linking different etiological insults to a common inflammatory and barrier-failure phenotype. A critical 
appraisal of contemporary and emerging therapeutic approaches is presented, covering conventional acid 
suppressive agents (antacids, histamine-2 receptor antagonists, proton pump inhibitors and potassiumcompetitive acid blockers), cytoprotective compounds and Helicobacter pylori eradication regimens, 
as well as the growing challenge of antimicrobial resistance. Emerging approaches are reviewed for 
translational potential, including nanoparticle-based drug delivery, probiotic adjuvants, phytochemical 
and herbal agents, Helicobacter pylori vaccines, microbiome-targeted therapies, and pharmacogenomically 
guided therapy. This review integrates molecular pathophysiology with therapeutic decision-making to 
provide an updated, mechanistically grounded framework for the management of gastric ulcer disease 
and identifies priority areas for future investigation