NSAID-INDUCED GASTRIC ULCERATION: PATHOPHYSIOLOGICAL MECHANISMS, THERAPEUTIC CHALLENGES AND POTENTIAL OF NATURAL PRODUCTS

Non-steroidal anti-inflammatory drugs (NSAIDs) are extensively prescribed for the treatment of pain and inflammatory conditions; however, their prolonged or inappropriate use can compromise gastric mucosal integrity and contribute to the development of gastric ulcers and other gastrointestinal complications. NSAID-associated gastric injury results from a combination of interacting events rather than a single mechanism. Suppression of cyclooxygenase-dependent prostaglandin synthesis weakens important endogenous defense mechanisms, while oxidative imbalance, inflammatory signalling, altered mucosal circulation, epithelial dysfunction, and increased cellular damage further contribute to ulcer development. Conventional gastroprotective medicines are effective in reducing gastric injury, but their use may be limited by adverse effects, drug interactions, recurrence, or concerns associated with prolonged therapy. These limitations have encouraged research into naturally derived compounds with broader biological activities. Various phytochemicals, including flavonoids, polyphenols, terpenoids, alkaloids, and saponins, have demonstrated gastroprotective potential through antioxidant, anti-inflammatory, cytoprotective, acid-regulating, and mucosal barrier-supporting actions in experimental studies. Recent investigations have also highlighted molecular pathways involving nuclear factor erythroid 2-related factor 2, nuclear factor-κB, nitric oxide signalling, NLRP3 inflammasome activation, mitochondrial dysfunction, and epithelial barrier regulation as potential targets for intervention. The present review examines the development of NSAID-induced gastric ulceration, underlying cellular and molecular mechanisms, commonly employed experimental models, and currently available pharmacological approaches. Particular attention is given to natural products and their proposed mechanisms of gastric protection, together with issues related to extract standardization, safety, dose optimization, and translation of preclinical findings into clinical applications. The review further identifies important research gaps and discusses future opportunities for developing evidence-based natural gastroprotective strategies.