Hesperidin blocks the gastritis-to-gastric cancer cascade: multi-pathway regulation and mechanism

Gastric cancer is a highly malignant tumor, and Correa's cascade reveals the progression of intestinal-type gastric cancer. Developing multi-targeted agents is key to gastric cancer prevention and treatment. Hesperidin has attracted considerable attention for its anti-inflammatory, antioxidant, and anti-angiogenic effects in gastric cancer prevention and treatment. This study investigates the regulatory mechanisms of Hesperidin in gastric cancer development by targeting multiple signaling pathways. In chronic mucosal inflammation, hesperidin targets multiple signaling pathways, including Drp, ERK/Nrf2, IL-10, HIF-1α, TNF, COX, and NF-κB. Through these pathways, it controls Helicobacter pylori infection, inhibits mitochondrial autophagy in Cajal interstitial cells, reduces oxidative stress, and thereby alleviates inflammation and promotes ulcer healing. In gastric cancer, hesperidin induces apoptosis, inhibits cell proliferation, and suppresses angiogenesis by regulating the MAPK, PI3K/Akt, Bcl-2, and ANGPT-TIE signaling pathways. Hesperidin is well-tolerated and has been shown to improve endothelial function, reduce inflammation, and alleviate oxidative stress in clinical trials of metabolic and cardiovascular diseases. It preserves a healthy gut microbiota and is supported by well-established extraction methods, making it a promising candidate for clinical translation in preventing the progression from gastritis to gastric cancer.