<![CDATA[Hyperuricemia is a metabolic disorder characterized by elevated uric acid levels and is associated with gout, oxidative stress, inflammation, and organ dysfunction. Piper betle L. (betel leaf) contains a variety of bioactive metabolites that may exert antihyperuricemic activity through inhibition of xanthine oxidase (XO), antioxidant activity, and other biological mechanisms. This study aimed to analyze the scientific evidence on the effects of P. betle on uric acid levels and on the activity of xanthine oxidoreductase enzymes, particularly XO and xanthine dehydrogenase (XDH), in hyperuricemia models. A systematic literature review was conducted in accordance with the PRISMA 2020 guidelines. The literature was searched in PubMed, Scopus, ScienceDirect, Google Scholar, and Garuda for articles published between 2021 and 2026. Articles were selected according to predefined inclusion and exclusion criteria, assessed for methodological quality and risk of bias, and synthesized narratively. A total of 482 articles were identified, of which 29 studies met the criteria for final synthesis. Overall, the findings indicate that P. betle has the potential to lower uric acid levels and inhibit XO activity. In vivo and in vitro evidence indicates that XO inhibition is the best-supported mechanism, whereas antioxidant activity and bioactive constituents appear to act as supporting mechanisms. Evidence regarding XDH remains limited. Heterogeneity in cultivar, plant part, extraction method, dose, hyperuricemia model, and outcome measures constitutes the principal limitation. P. betle is a promising candidate for development as a natural antihyperuricemic agent; however, standardization and further mechanistic validation are required.]]>
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