Fisetin

Fisetin (3,7,3′,4′-tetrahydroxyflavone) is a bioactive flavonol found at highest dietary concentration in strawberries and at lower levels in apples, persimmons, grapes, onions, and cucumbers. First isolated from the heartwood of Venetian sumac (Cotinus coggygria) in the late nineteenth century and characterized as a plant pigment, fisetin remained a minor flavonoid of limited pharmacological interest until convergent twenty-first-century discoveries established it as a multi-target agent active across the principal molecular pathways of cellular senescence, neurodegeneration, inflammation, and oncogenesis. The compound was identified as a potent senolytic in the landmark Zhu et al. (2017) screen at the Mayo Clinic Robert and Arlene Kogod Center on Aging, and the subsequent Yousefzadeh et al. (2018) demonstration that late-life oral fisetin administration extended median and maximum lifespan in wild-type mice while reducing senescence-associated markers in multiple tissues positioned it as the leading dietary flavonoid candidate for translational senolytic therapy [1, 2]. Mechanistically, fisetin operates through a convergent multi-pathway pharmacology: it inhibits PI3K/Akt/mTOR signaling by direct suppression of PI3K catalytic and regulatory subunit expression and by activation of the mTOR repressor TSC2 through concurrent AMPK phosphorylation; it activates SIRT1-dependent deacetylation cascades that suppress NF-kappaB transcriptional activity and the senescence-associated secretory phenotype (SASP); it induces Nrf2 nuclear translocation and downstream phase II antioxidant enzyme expression; and it modulates the Bcl-2 family balance toward pro-apoptotic signaling selectively in senescent cells [3, 4, 5]. The neuroprotective profile has been extensively characterized by the Maher laboratory at the Salk Institute for Biological Studies, where fisetin and its optimized derivative CMS121 have demonstrated efficacy in transgenic Alzheimer’s disease mouse models through reduction of lipid peroxidation via fatty acid synthase (FASN) inhibition, suppression of neuroinflammatory cascades, and maintenance of glutathione homeostasis [6, 7]. CMS121 completed a Phase 1 clinical trial in 2025, with single doses up to 1800 mg and repeat doses up to 900 mg per day for 7 days demonstrating acceptable tolerability and favorable pharmacokinetic parameters in healthy volunteers [8]. The anticancer pharmacology spans preclinical efficacy in prostate, breast, colorectal, lung, melanoma, pancreatic, and bladder cancer models, principally through cell cycle arrest at G2/M and G1/S checkpoints, mitochondrial apoptosis induction, and suppression of epithelial-mesenchymal transition and matrix metalloproteinase expression [9, 10]. Clinical translation is constrained by the poor oral bioavailability characteristic of hydroxylated flavonols: fisetin undergoes rapid and extensive phase II conjugation (glucuronidation and sulfation) in the intestinal epithelium and liver, producing low systemic free flavonol concentrations after oral dosing; multiple formulation strategies (nanocochleates, liposomes, nanoemulsions, hybrid hydrogels) have demonstrated 10- to 140-fold bioavailability enhancement in preclinical and early human pharmacokinetic studies [11, 12]. Clinical trials led by the Kirkland laboratory at Mayo Clinic are evaluating fisetin at oral doses of 20 mg/kg per day for senolytic indications including frailty in aging (AFFINITY trial, NCT03675724), COVID-19 in skilled nursing facilities, and sepsis in elderly patients (STOP-Sepsis, NCT05758246) [13, 14]. This monograph reviews the chemistry, natural sourcing, and structural pharmacology of fisetin; the multi-pathway molecular mechanism across senescence, inflammation, neuroprotection, and oncogenesis; the pharmacokinetic limitations and formulation solutions; the preclinical evidence base across aging, neurodegeneration, and cancer; the clinical trial landscape; sourcing and quality verification for research applications; reconstitution and handling; stack interactions; adverse-event signal; and a comparative assessment of five senolytic or flavonoid candidates against fisetin on five competency standards.