Natural flavonoids in peptic ulcer disease: preclinical evidence for gastroprotection versus healing of established ulcers

Peptic ulcer disease (PUD) is a global health concern with a lifetime prevalence of 5%–10%. Current therapies may be limited by adverse effects and the increasing prevalence of drug-resistant Helicobacter pylori strains, highlighting the need for safer complementary approaches. Natural flavonoids have emerged as candidate bioactive compounds with gastroprotective properties in preclinical models. This systematic review, conducted according to PRISMA 2020, summarizes preclinical evidence published between 2020 and 2025 on the gastroprotective (preventive) and ulcer-healing effects of isolated and chemically characterized flavonoids. PubMed, Scopus, and ScienceDirect were searched, and eligible studies were restricted to in vitro and/or in vivo experimental investigations. Fourteen studies were included, and their risk of bias was assessed using the SYRCLE and ToxRTool tools. Gastric injury was induced mainly by ethanol, indomethacin, aspirin, or acetic acid in rats and mice, complemented by two gastric cell models. Seven of the 13 in vivo studies used preventive protocols, whereas only four evaluated the healing of established ulcers; the remaining studies used concurrent, post-injury, or mixed protocols. Quercetin (three studies), apigenin, and myricetin (two studies each) were the most frequently investigated, whereas luteolin, naringenin, acacetin, rhamnetin, fisetin, genistein, and malvidin were each evaluated in a single study. These compounds were associated with reduced mucosal damage and with changes in markers of oxidative stress, inflammation, apoptosis, and mucosal defense; potential anti- H. pylori mechanisms are discussed on the basis of previous reviews. Overall, the available evidence supports gastroprotective activity of natural flavonoids in preclinical models, whereas evidence for ulcer healing remains limited. Most studies were rated as having an unclear risk of bias, and differences in models, doses, treatment timing, and bioavailability limit direct comparison between compounds. These preclinical findings cannot be considered evidence of clinical efficacy, and pharmacokinetic, safety, and well-designed clinical studies are required before any therapeutic use in PUD can be considered.