Naringenin-loaded liposomal nanoparticles attenuate chemotherapy-induced gastric mucositis: Histopathological and ultrastructural evidence with modulation of NRF2/HO-1, NF-κB/COX-2, and apoptotic pathways.

Chemotherapy-induced gastric mucositis is a frequent complication of 5-fluorouracil (5-FU) treatment, characterized by severe histopathological and ultrastructural injury accompanied by oxidative stress, inflammation, apoptosis, and disruption of the gastric mucosal barrier. The present study investigated the gastroprotective effect of naringenin-loaded liposomal nanoparticles (NAR-LNPs) against 5-FU-induced gastric injury in rats and compared their efficacy with free naringenin (NAR). NAR-LNPs were prepared using a modified thin-film hydration method and characterized before biological evaluation. Sixty adult male Sprague-Dawley rats were randomly assigned to six experimental groups. Gastric mucositis was induced by a single intraperitoneal injection of 5-FU (400 mg/kg), while NAR or NAR-LNPs (100 mg/kg/day) were administered orally for seven consecutive days. Histopathological examination revealed extensive gastric mucosal erosion, glandular degeneration, inflammatory cell infiltration, and epithelial disruption following 5-FU administration, whereas transmission electron microscopy demonstrated marked subcellular damage, including mitochondrial swelling and loss of cellular integrity. NAR-LNPs provided greater protection than free NAR, markedly preserving gastric tissue architecture and ultrastructure and restoring gastric pH and serum gastrin toward control levels. NAR-LNPs also reduced oxidative and inflammatory disturbances, restored NRF2/HO-1-associated antioxidant responses, decreased NF-κB/COX-2-associated inflammatory signaling, reduced Bax and caspase-3 while restoring Bcl-2, and recovered gastric MUC5AC and PGE₂ levels. Collectively, NAR-LNPs provided superior gastroprotection compared with free NAR, with preservation of gastric morphology accompanied by coordinated improvement in antioxidant defense, inflammatory responses, apoptosis-associated signaling, and mucosal defense. These findings support NAR-LNPs as a promising formulation for further investigation in chemotherapy-induced gastric mucosal injury.