Among medicinal plants, the genus Smilax (family Smilacaceae) is widely distributed across all continents except Antarctica, with its rhizomes being the primary source of commercial and therapeutic value. Smilax has been traditionally used for centuries to treat a range of ailments, including diabetes, gout, rheumatism, skin disorders, and syphilis. This review provides an updated, comprehensive, and categorized overview of the botany, traditional uses, phytochemistry, pharmacological activities, and toxicological profiles of Smilax species. To date, at least 1058 compounds have been identified from Smilax species, including flavonoids, phenolic acids, steroidal saponins, polysaccharides, and stilbenoids. These isolated constituents exhibit a broad spectrum of pharmacological activities, including anticancer, antidiabetic, anti-inflammatory, antimicrobial, antioxidant, antiviral, immunomodulatory, and hepatoprotective effects. Traditional knowledge, increasingly supported by pharmacological evidence, highlights the substantial therapeutic potential of Smilax species. However, most current findings are derived from preliminary in vitro and in vivo studies. Future research should focus on clinically relevant, mechanistic, and integrative approaches to fully elucidate therapeutic potential and facilitate the development of evidence-based applications.
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