Comprehensive Monograph on Fisetin (DB07795)

Executive Summary

Fisetin (3,3',4',7-Tetrahydroxyflavone) is a naturally occurring small molecule, classified as a plant flavonol, that has garnered significant scientific interest for its broad spectrum of biological activities. Preclinical research has positioned Fisetin as a highly promising agent, particularly for its potent senolytic properties—the ability to selectively clear dysfunctional, senescent cells that contribute to aging and chronic disease. In animal models, this activity has been linked to remarkable extensions in both healthspan and lifespan. Furthermore, extensive in vitro and in vivo studies have elucidated its multi-target mechanisms as a potent anti-inflammatory, antioxidant, and anti-neoplastic compound, primarily through the modulation of critical cellular signaling pathways, including inhibition of Cyclin-dependent kinase 6 (CDK6) and regulation of NF-κB, PI3K/Akt/mTOR, and Nrf2 pathways.[1]

Despite this compelling preclinical portfolio, the therapeutic potential of Fisetin is fundamentally constrained by its challenging biopharmaceutical properties. The molecule exhibits extremely poor oral bioavailability, a consequence of low aqueous solubility and, more critically, rapid and extensive first-pass metabolism in the gut and liver, where it is converted into inactive glucuronide and sulfate conjugates.[5] This pharmacokinetic barrier renders the therapeutic dosages used in research unattainable through dietary intake alone and has historically limited its clinical translation.