Shahrekord University of Medical Sciences Journal of Herbmed Pharmacology 2345-5004 15 4 2026 10 01 A systematic review of fisetin in oral premalignant and malignant disorders: Molecular mechanisms and therapeutic potential 420 432 10.34172/jhp.53989 EN Mehran Taheri Khafri https://orcid.org/0009-0002-8065-7311 Zahra Khiali https://orcid.org/0009-0003-0001-0620 Kosar Farhadi Babadi https://orcid.org/0000-0002-3607-2298 Journal Article 10.34172/jhp.53989 2026 06 09 2026 08 10 Introduction: Oral cavity neoplasms pose a public health concern worldwide. We aimed to systematically review the current molecular mechanisms and preclinical efficacy of fisetin (FIS) in oral premalignant and malignant disorders. Methods: A systematic review was conducted following the PRISMA guidelines, and keyword searches were performed in electronic databases such as PubMed, Scopus, Cochrane Library, and Web of Science. After screening the publications based on the inclusion and exclusion criteria, the desired data were extracted from the articles and recorded. Also, the risk of bias assessment was conducted using the Quality Assessment Tool for In Vitro Studies (QUIN) and the SYRCLE Risk of Bias tool. Results: FIS exerts anticancer effects against oral premalignant lesions and oral squamous cell carcinoma (OSCC) via multiple pathways, such as the induction of apoptotic processes, endoplasmic reticulum (ER) stress, and autophagy, accompanied by mitochondrial dysfunction, reactive oxygen species (ROS) generation, DNA breakage, and activation of caspase-dependent signaling. It prohibits tumor cell proliferation due to cell-cycle arrest and suppression of key oncogenic pathways, including RTK/Met-Src, EGFR/Akt/ERK/STAT3, mTOR, and PAK4 signaling. Furthermore, FIS reduces migration, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, and cancer stemness while enhancing antioxidant and detoxification defenses in normal cells. Conclusion: Preclinical evidence suggests that FIS possesses promising chemopreventive and anticancer properties against premalignant and malignant disorders. However, clinical studies are needed for its clinical application.