| Summary: | Abstract Fisetin is one of the most popular flavonoids found in vegetables and fruits with several health benefits such as antidiabetic, anticancer, and anti‐inflammatory activities. Biotechnology or chemosynthesis tools were used for the synthesis of fisetin and its analogs to improve their yield and efficacy. Structure activity relationships (SARs) revealed that the aromatic hydroxyl groups especially the 3,4‐dihydroxylation at ring B were crucial for fisetin biological activities, whereas substitution of several hydroxyl groups in fisetin appeared to impact its original effects. The ongoing or upcoming clinical trials containing fisetin are applied in drugs and dietary supplements. Noteworthily, fisetin has been successfully incorporated into nutraceuticals in the market. Furthermore, the delivery system of fisetin‐loaded nanocochleates showed the best bioavailability compared to other formulations. This review presents the latest research progress of fisetin on its synthesis, structure–activity relationships, pharmacokinetics, biological activities, and underlying mechanisms, bioavailability, delivery systems, and clinical trials to provide a comprehensive insight into the research and application of this valuable natural compound.
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