Phytochemical-driven angiogenesis and mucosal regeneration in gastric ulcer healing: molecular mechanisms, preclinical evidence, and translational perspectives.

Gastric ulcer remains a significant global gastrointestinal condition characterized by disruption of the gastric mucosal barrier, attributed to oxidative stress, inflammation, Helicobacter pylori infection, nonsteroidal anti-inflammatory drugs (aspirin, indomethacin, diclofenac), and compromised tissue repair. While traditional therapies effectively reduce acid secretion and eliminate H. pylori, they often do not actively promote mucosal regeneration and angiogenesis, both of which are crucial for the complete healing of ulcers and the prevention of recurrence. This review integrates molecular mechanisms, preclinical and clinical evidence, advanced delivery strategies, and future translational perspectives to provide a comprehensive overview of phytochemical-mediated gastric ulcer healing. Recent findings suggest that tissue repair mediated by angiogenesis, which is regulated by vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1α, nitric oxide, prostaglandins, NF-κB, PI3K/Akt, modulated mitogen-activated protein kinase (MAPK), and fibroblast growth factors, plays a pivotal role in the restoration of the gastric mucosa. Phytochemicals, such as polyphenols, flavonoids, terpenoids, alkaloids, and other bioactive compounds derived from plants, have shown considerable gastroprotective and pro-healing effects in experimental models. Compounds like curcumin, quercetin, naringin, asiaticoside (20 mg/kg, in rats), glycyrrhizin, berberine, and sulforaphane enhance VEGF expression, promote microvascular regeneration, stimulate epithelial restitution, and restore redox balance, thus expediting the healing of ulcers. Moreover, innovative drug delivery methods enhance the bioavailability and therapeutic effectiveness of phytochemicals. They may be promising adjunctive therapeutic agents for gastric ulcer healing through their ability to modulate mucosal regeneration. Integration of advanced methods, biomarker-based clinical studies, systems biology, and the potential of emerging precision medicine strategies may accelerate translational applications and improve future gastric ulcer management strategies.