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.

In response, recent innovation has focused on developing advanced formulations, such as liposomal encapsulation and combination with fenugreek galactomannans, which have been shown to dramatically enhance systemic absorption.[7] This breakthrough has renewed clinical interest, with a growing number of human trials investigating Fisetin's efficacy in specific, senescence-driven conditions like post-chemotherapy frailty, vascular aging, and inflammation in older adults.[9] Concurrently, the commercial landscape is maturing, with the first branded Fisetin ingredient recently achieving Self-Affirmed Generally Recognized as Safe (SA-GRAS) status, signaling a shift toward higher standards of quality and safety in the dietary supplement market.[11] Ultimately, Fisetin stands as a molecule of immense promise but significant complexity. Its future as a clinically relevant agent depends entirely on the successful validation of its preclinical efficacy in robust human trials and the continued development of safe and effective bioavailability-enhanced delivery systems.

Section 1: Chemical Identity and Physicochemical Profile

A comprehensive understanding of Fisetin's therapeutic potential begins with a precise characterization of its chemical and physical properties. These fundamental attributes govern its stability, solubility, and interactions with biological systems, forming the basis of its pharmacokinetic and pharmacodynamic profile.

1.1 Nomenclature and Identifiers

To ensure unambiguous identification across scientific literature and regulatory databases, Fisetin is cataloged under several standardized names and codes.

• Primary Generic Name: Fisetin.[1]
• Systematic IUPAC Name: 2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one.[2]
• Chemical Abstracts Service (CAS) Number: 528-48-3.[2]
• DrugBank Accession Number: DB07795.[1]
• PubChem Compound ID (CID): 5281614.[12]
• Synonyms: Fisetin is also known by a wide array of synonyms derived from its chemical structure and historical use. These include: 3,3',4',7-Tetrahydroxyflavone, 5-Desoxyquercetin, 2-(3,4-Dihydroxyphenyl)-3,7-dihydroxy-4H-1-benzopyran-4-one, Cotinin (distinct from cotinine), Fustel, Superfustel, Fisetholz, and the color index designation C.I. 75620.[1]
• Other Key Identifiers: For comprehensive cross-referencing, other relevant database codes include ChEBI (CHEBI:42567), ChEMBL (CHEMBL31574), and UNII (OO2ABO9578).[2]

1.2 Molecular Structure and Chemical Formula

Fisetin's biological activity is a direct consequence of its distinct molecular architecture.

• Chemical Formula: The empirical formula for Fisetin is .[1]
• Structural Description: Fisetin is a member of the flavonol subclass of flavonoids. Its core structure consists of a 2-phenyl-1-benzopyran-4-one backbone, which is composed of two aromatic rings (A and B) linked by a three-carbon heterocyclic pyran ring (C).[1] It is specifically defined as a 7-hydroxyflavonol with three additional hydroxyl ( ) groups located at positions 3, 3', and 4'.[2] The presence of the hydroxyl group at the 3-position is the defining characteristic of a flavonol. The adjacent hydroxyl groups at the 3' and 4' positions on the B-ring form a catechol moiety, which is a critical functional group for its potent antioxidant and free-radical scavenging activities.
• Standardized Representations: For computational and database purposes, its structure is represented by the following identifiers:
• Canonical SMILES: C1=CC(=C(C=C1C2=C(C(=O)C3=C(O2)C=C(C=C3)O)O)O)O.[2]
• InChIKey: XHEFDIBZLJXQHF-UHFFFAOYSA-N.[2]

1.3 Physicochemical Properties and Predictive Analytics

The physicochemical properties of Fisetin dictate its behavior in both formulation and biological environments. As summarized in Table 1, these parameters reveal a molecule with inherent challenges related to solubility and bioavailability, despite possessing some "drug-like" characteristics.

Fisetin presents as an ochre or yellow crystalline powder with a melting point of approximately 330 °C.[3] Its very low aqueous solubility is a primary obstacle to its formulation and oral absorption.[1] While it is soluble in organic solvents like dimethyl sulfoxide (DMSO) and ethanol, this is of limited utility for standard oral dosage forms.[15] Its moderate lipophilicity, indicated by a logP around 2, suggests it should be capable of passive diffusion across cell membranes.[1]

Predictive pharmacokinetic models offer a conflicted view of Fisetin's potential. Its compliance with Lipinski's Rule of Five suggests that, based on molecular size and polarity, it should possess favorable properties for oral absorption and permeation.[1] This rule is a widely used heuristic in drug discovery to forecast the "drug-likeness" of a molecule. However, this prediction stands in stark contrast to the extensive empirical evidence demonstrating Fisetin's exceptionally poor oral bioavailability.[5] This discrepancy underscores a critical limitation of simple predictive rules, which often fail to account for the complex biological processes that govern a drug's fate

in vivo. In the case of Fisetin, the "drug-like" characteristics suggested by its molecular weight and lipophilicity are completely overshadowed by its profound metabolic instability. The molecule is a substrate for rapid and extensive first-pass metabolism, a factor not captured by the Rule of Five but which serves as the dominant barrier to its systemic delivery and therapeutic efficacy. This highlights that for flavonoids and many other natural products, metabolic susceptibility, rather than passive permeability alone, is the principal determinant of oral bioavailability.

Property	Value	Source
Molecular Formula		1
Average Molecular Weight	286.2363 g/mol	1
Monoisotopic Mass	286.047738052 Da	1
Physical Appearance	Ochre/Yellow Crystalline Powder	3
Melting Point	330 °C (626 °F)	13
Water Solubility	0.151 mg/mL (predicted)	1
logP (Lipophilicity)	2.03 (ALOGPS); 1.81 (Chemaxon)	1
pKa (Strongest Acidic)	6.32 (predicted)	1
Physiological Charge	-1 (predicted)	1
Hydrogen Bond Donors	4	1
Hydrogen Bond Acceptors	6	1
Rotatable Bond Count	1	1
Polar Surface Area	107.22 Ų	1
Rule of Five Compliance	Yes	1
Veber's Rule Compliance	No	1
Ghose Filter Compliance	Yes	1

Section 2: Botanical Origin and Natural Occurrence

Fisetin is not a synthetic compound but a product of plant secondary metabolism, found widely, albeit in low concentrations, throughout the plant kingdom. Its presence in the human diet is the historical basis for its investigation as a health-promoting agent.

2.1 Classification as a Flavonol

Fisetin belongs to the flavonoid group of polyphenols, a large and diverse class of phytochemicals known for their vibrant colors and significant biological activities.[16] Specifically, Fisetin is classified as a flavonol, a subgroup characterized by a 3-hydroxyflavone backbone.[1] This classification is functionally important, as flavonols, including structurally similar compounds like quercetin and kaempferol, are among the most extensively studied flavonoids and are recognized for their potent antioxidant, anti-inflammatory, and cell-regulating properties.[17] In nature, Fisetin often serves as a yellow or ochre pigment, contributing to the coloration of various plant tissues.[13] Its role as a pigment is reflected in its historical use as the source of the traditional yellow dye known as "young fustic," derived from the wood of the Eurasian smoketree (

Rhus cotinus).[13]

2.2 Primary Dietary Sources and Concentration Variability

Fisetin is present in a variety of common fruits and vegetables, but its concentration varies dramatically between sources.[2]

• Richest Dietary Source: Strawberries (Fragaria sp.) are consistently identified as the food with the highest concentration of Fisetin, containing approximately 160 micrograms per gram () of fresh weight.[13]
• Other Dietary Sources: While many other foods contain Fisetin, the levels are substantially lower. Notable sources include apples (), persimmons (), grapes (), onions (), and cucumbers ().[13]
• Botanical Sources: Beyond common foods, Fisetin is synthesized by a range of plants, including trees and shrubs from the Fabaceae and Anacardiaceae families, such as acacia species and the Quebracho colorado tree.[13] It was first isolated in 1833 from the Venetian sumach ( Rhus cotinus L.).[14]

The natural occurrence of Fisetin in the diet has led to an average daily human intake estimated to be only around 0.4 milligrams.[19] This dietary level of exposure creates a significant disconnect when compared to the doses required to elicit the biological effects observed in scientific research. To achieve even a low-end supplemental dose of 100 mg, an individual would need to consume over 600 grams (approximately 1.4 pounds) of strawberries, the richest known source.[18] For the high-dose senolytic protocols used in some studies, which can be 1,000 mg or more, the dietary equivalent would be over 6 kilograms (more than 13 pounds) of strawberries.[22] This calculation makes it unequivocally clear that it is impossible to achieve the pharmacologically active doses of Fisetin being investigated for therapeutic purposes through diet alone. This reality fundamentally reframes the discussion around Fisetin's benefits, moving it from the realm of nutrition to that of pharmacology, where its effects are contingent upon administration as a purified, high-dose supplement.

Section 3: Pharmacodynamics and Molecular Mechanisms of Action

Fisetin is a pleiotropic molecule that exerts its diverse biological effects by interacting with a wide array of molecular targets and signaling pathways. Its pharmacodynamic profile is characterized by its ability to modulate key processes involved in cell cycle regulation, senescence, inflammation, oxidative stress, and cancer progression.

3.1 Primary Target Engagement: Cyclin-Dependent Kinase 6 (CDK6) Inhibition

A key, well-defined molecular target of Fisetin is Cyclin-dependent kinase 6 (CDK6), a crucial enzyme in the regulation of cell division.[1] Fisetin acts as a direct inhibitor of CDK6.[1] The CDK6 enzyme forms a complex with cyclin D proteins, and this complex is responsible for phosphorylating the retinoblastoma protein (pRb), a critical step that allows cells to progress from the G1 (growth) phase to the S (synthesis) phase of the cell cycle. By inhibiting the CDK6/cyclin D complex, Fisetin effectively blocks this transition, leading to cell cycle arrest in the G1 phase.[25] This mechanism is a cornerstone of its anti-proliferative and anti-cancer activities, as uncontrolled cell cycle progression is a hallmark of cancer. The direct binding and inhibition of CDK6 kinase activity by Fisetin have been confirmed through co-crystallization studies, providing strong evidence for this specific target engagement.[24]

3.2 Senolytic Mechanisms: Selective Induction of Apoptosis in Senescent Cells

One of the most compelling aspects of Fisetin's activity is its function as a potent senolytic agent.[4] Senescent cells are damaged or stressed cells that have permanently exited the cell cycle but remain metabolically active and resistant to apoptosis (programmed cell death).[7] These "zombie" cells accumulate in tissues with age and secrete a cocktail of pro-inflammatory molecules known as the Senescence-Associated Secretory Phenotype (SASP), which promotes chronic inflammation, tissue degradation, and is considered a key driver of aging and many age-related diseases.[7]

Fisetin has been identified as the most potent senolytic among a panel of ten tested flavonoids, surpassing even other well-known compounds like quercetin.[4] It acts by selectively inducing apoptosis in these otherwise apoptosis-resistant senescent cells, thereby clearing them from tissues.[7] This "hit-and-run" mechanism reduces the overall burden of senescent cells and the associated inflammatory SASP, leading to a restoration of tissue homeostasis.[4] In preclinical models, this senolytic action has been directly linked to reduced age-related pathology and a significant extension of both healthspan and lifespan in aged mice.[4]

The molecular mechanisms underlying Fisetin's senolytic and anti-cancer effects are deeply interconnected and likely synergistic. Senescent cells share key characteristics with cancer cells, notably a strong resistance to apoptosis that is maintained by the upregulation of pro-survival signaling pathways. The same molecular actions that Fisetin employs to kill cancer cells—such as the induction of caspase-mediated apoptosis and the inhibition of pro-survival pathways like PI3K/Akt—are likely repurposed to overcome this resistance and eliminate senescent cells.[2] This dual functionality is of particular therapeutic interest in oncology. Cancer treatments like chemotherapy can themselves induce senescence in a subset of tumor cells, which can paradoxically promote cancer relapse and contribute to treatment-related side effects like frailty.[26] Fisetin's ability to potentially kill residual cancer cells while simultaneously clearing these therapy-induced senescent cells provides a powerful scientific rationale for its investigation in post-chemotherapy settings, a hypothesis that is being directly tested in several ongoing human clinical trials.[9]

3.3 Anti-inflammatory Activity: Modulation of NF-κB, MAPK, and Cytokine Signaling

Fisetin exhibits robust anti-inflammatory properties by targeting several core inflammatory signaling cascades.[2]

• NF-κB Pathway Inhibition: A central mechanism of its anti-inflammatory action is the potent inhibition of the Nuclear Factor kappa B (NF-κB) signaling pathway.[2] NF-κB is a master transcription factor that, when activated, moves into the nucleus and orchestrates the expression of a vast array of pro-inflammatory genes, including cytokines, chemokines, and enzymes like cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Fisetin has been shown to block the activation and nuclear translocation of NF-κB, thereby suppressing the entire downstream inflammatory cascade.[18]
• Cytokine and Mediator Suppression: As a consequence of NF-κB inhibition and other effects, Fisetin directly reduces the production of key pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and Interleukin-1 beta (IL-1β).[2]
• MAPK Pathway Modulation: Fisetin also regulates the Mitogen-Activated Protein Kinase (MAPK) signaling pathway, which includes kinases like p38, JNK, and ERK1/2.[3] This pathway is another critical hub for cellular responses to stress and inflammation, and its modulation by Fisetin contributes to its overall anti-inflammatory effect.

3.4 Antioxidant Properties: Direct Radical Scavenging and Upregulation of Endogenous Defenses

Fisetin combats oxidative stress through a powerful dual-action mechanism, acting as both a direct and indirect antioxidant.[2]

• Direct Scavenging of Free Radicals: The chemical structure of Fisetin, particularly its catechol group on the B-ring and the 3-hydroxyl group, allows it to directly donate hydrogen atoms to neutralize reactive oxygen species (ROS) and other free radicals, thus preventing them from damaging cellular components like DNA, lipids, and proteins.[2]
• Upregulation of Endogenous Antioxidant Systems: Perhaps more significantly, Fisetin enhances the body's intrinsic antioxidant defense systems. It achieves this by activating the Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway.[3] Nrf2 is a transcription factor that controls the expression of a suite of antioxidant and detoxification enzymes. Furthermore, Fisetin has been shown to increase intracellular levels of glutathione (GSH), often referred to as the body's "master antioxidant," further bolstering cellular resilience against oxidative stress.[2]

3.5 Anti-neoplastic Pathways: Impact on Cell Cycle, Apoptosis, and Metastasis

In addition to its direct inhibition of CDK6, Fisetin disrupts cancer cell viability through a multitude of interconnected pathways.[18]

• Induction of Apoptosis: Fisetin is a potent inducer of apoptosis in various cancer cell lines. It triggers both the extrinsic and intrinsic apoptotic pathways, activating key executioner enzymes like caspase-3, caspase-8, and caspase-9, while simultaneously inhibiting anti-apoptotic proteins such as Bcl-2.[2]
• Inhibition of Pro-Survival Signaling: It effectively blocks the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt)/mammalian Target of Rapamycin (mTOR) pathway. This is one of the most critical intracellular signaling cascades that promotes cell growth, proliferation, and survival, and its dysregulation is a common feature of many cancers.[3]
• Anti-Metastatic and Anti-Angiogenic Effects: Fisetin can inhibit the processes of cancer cell invasion and metastasis. It achieves this by downregulating the expression and activity of enzymes that degrade the extracellular matrix, such as Matrix Metalloproteinases (MMP-2, MMP-9) and urokinase Plasminogen Activator (uPA).[18] It also demonstrates anti-angiogenic properties, inhibiting the formation of new blood vessels that tumors require to grow and spread.[7]

Target/Pathway	Effect of Fisetin	Associated Biological Activity	Key Sources
Cell Cycle Regulation
Cyclin-Dependent Kinase 6 (CDK6)	Inhibition	Anti-proliferative, Anti-cancer	1
Cellular Senescence
Senescent Cells	Selective induction of apoptosis	Senolytic, Anti-aging	4
Inflammation Signaling
NF-κB Pathway	Inhibition	Anti-inflammatory	2
Pro-inflammatory Cytokines (TNF-α, IL-6)	Decreased production	Anti-inflammatory	2
MAPK Pathway (p38, JNK, ERK)	Modulation/Inhibition	Anti-inflammatory, Anti-cancer	3
Oxidative Stress Response
Reactive Oxygen Species (ROS)	Direct scavenging	Antioxidant	2
Nrf2 Pathway	Activation	Indirect Antioxidant	3
Glutathione (GSH)	Increased levels	Indirect Antioxidant	2
Cancer Pro-Survival Pathways
PI3K/Akt/mTOR Pathway	Inhibition	Anti-cancer, Apoptosis induction	3
Apoptotic Machinery (Caspases, Bcl-2)	Activation of caspases, Inhibition of Bcl-2	Apoptosis induction, Anti-cancer	2
Metastasis & Angiogenesis
MMPs, uPA	Downregulation	Anti-metastatic	18
VEGF	Downregulation	Anti-angiogenic	24

Section 4: Pharmacokinetics, Metabolism, and Bioavailability

While Fisetin's pharmacodynamic profile is impressive, its utility as an oral therapeutic agent is severely limited by its challenging pharmacokinetic properties. The absorption, distribution, metabolism, and excretion (ADME) profile of Fisetin is characterized by poor oral bioavailability, which stands as the single greatest obstacle to its clinical development.

4.1 Absorption, Distribution, Metabolism, and Excretion (ADME) Profile

• Absorption: In silico models predict that Fisetin has high human intestinal absorption potential and the ability to cross the blood-brain barrier.[1] However, these favorable passive diffusion characteristics are not realized in practice due to overwhelming metabolic and efflux processes in the gastrointestinal tract.
• Metabolism: Upon oral ingestion, Fisetin is subject to immediate and extensive first-pass metabolism.[5] Enzymes in the intestinal wall and the liver, primarily UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), rapidly conjugate the hydroxyl groups of the Fisetin molecule, converting it into water-soluble and largely inactive sulfate and glucuronide metabolites.[5] This biotransformation is so efficient that the parent, active form of Fisetin is often found only transiently or at undetectable levels in the systemic circulation following an oral dose.[5]
• Distribution and Excretion: Due to its rapid metabolism, the distribution of free Fisetin throughout the body is minimal. Animal studies have reported an extremely short intravenous half-life of just a few minutes for the parent compound, indicating rapid clearance from the bloodstream.[5] The conjugated metabolites are more readily excreted, primarily via urine and bile.

4.2 The Challenge of Low Oral Bioavailability

The confluence of Fisetin's poor aqueous solubility and its extensive pre-systemic (first-pass) metabolism results in extremely low and erratic oral bioavailability.[5] This means that when Fisetin is consumed orally in its pure, unformulated state, only a very small fraction of the dose reaches the systemic circulation in its active form. This issue is not unique to Fisetin but is a common challenge for many polyphenolic compounds.[39] In addition to metabolic degradation, animal studies suggest that the P-glycoprotein (P-gp) efflux pump in the intestinal lining may actively transport Fisetin back into the gut lumen, further limiting its absorption.[5] Predictive models support this, identifying Fisetin as a likely P-gp substrate.[1]

4.3 Advanced Formulation Strategies for Bioavailability Enhancement

The critical need to overcome Fisetin's poor bioavailability has spurred significant research into advanced drug delivery systems. The goal of these technologies is to protect the Fisetin molecule from metabolic degradation and enhance its absorption into the bloodstream.

• Liposomal Formulations: One promising approach is the encapsulation of Fisetin within liposomes, which are microscopic vesicles composed of a lipid bilayer. In animal models, intraperitoneal administration of liposomal Fisetin resulted in significantly higher and more sustained plasma concentrations compared to free Fisetin, even when administered at a dose ten times lower. This improved bioavailability translated directly into enhanced anti-tumor activity.[8]
• Fenugreek Galactomannan Formulation: A particularly successful strategy demonstrated in humans involves combining Fisetin with galactomannans, a type of fiber isolated from fenugreek seeds. This formulation protects Fisetin from enzymatic modification in the gut. A human clinical study found that this combination increased the bioavailability of Fisetin by approximately 25 times compared to an equivalent dose of standard Fisetin, as measured by both the maximum plasma concentration () and the total drug exposure over time (AUC).[5]
• Other Nanodelivery Technologies: The field of nanomedicine offers several other potential strategies for improving Fisetin's delivery, including the use of polymer nanoparticles, complexes with cyclodextrins (which can increase solubility), and the formulation of nanocrystals.[38]

The development and adoption of these bioavailability-enhanced formulations represent a paradigm shift for Fisetin. While they hold the key to unlocking its therapeutic potential, they also fundamentally alter its safety profile. The "natural" safety of unformulated Fisetin is, to a large extent, a consequence of its poor absorption; the body's metabolic machinery effectively limits systemic exposure. By successfully bypassing these natural defense mechanisms, advanced formulations can achieve plasma concentrations that are orders of magnitude higher than what was previously possible. This dramatically increases the potential for both on-target efficacy and off-target toxicity, as well as clinically significant drug-drug interactions. The potent inhibition of Cytochrome P450 enzymes by Fisetin, which may be negligible at the low systemic levels achieved with standard formulations, could become a critical safety concern at 25-fold higher concentrations. Therefore, these novel formulations cannot be viewed as simple dietary supplements. They must be evaluated with the full pharmacological and toxicological rigor applied to new pharmaceutical drugs, with a particular emphasis on conducting thorough drug interaction studies to ensure their safe use.

Section 5: Review of Preclinical and Clinical Evidence

For decades, Fisetin has been the subject of extensive laboratory research, building a robust portfolio of preclinical evidence across a range of disease models. However, the translation of these promising findings into proven human benefits has been slow, with rigorous clinical trials only emerging in recent years. As of 2018, there was no definitive clinical evidence of its efficacy in humans.[13]

5.1 Preclinical Evidence in Aging and Longevity Models

The most compelling preclinical data for Fisetin lies in the field of geroscience. Landmark studies have demonstrated its profound effects on aging in animal models. In one key experiment, when Fisetin was administered to old mice, equivalent in age to 75-year-old humans, it extended their median and maximum lifespan by nearly 10%.[4] This remarkable effect was not merely an extension of life but also an improvement in healthspan. The treated animals showed reduced age-related pathology and a restoration of tissue homeostasis.[4] This benefit was observed even when the intervention was initiated late in life, a finding with significant implications for potential human application.[4] The underlying mechanism for this effect is believed to be Fisetin's potent senolytic activity—its ability to clear the senescent cells that drive the aging process.[4]

5.2 Investigational Use in Oncology

A vast body of in vitro and animal research has established Fisetin as a potential anti-neoplastic agent. It has demonstrated anti-proliferative and pro-apoptotic properties against a wide spectrum of cancer cell lines, including those from pancreatic, lung, breast, prostate, and colon cancers.[2] In animal xenograft models, treatment with Fisetin has been shown to significantly reduce tumor size and decrease the expression of proliferation-associated markers like PCNA and Ki67.[15] Its anti-cancer mechanisms are multifaceted, involving cell cycle arrest, apoptosis induction, and inhibition of metastasis and angiogenesis.[18]

5.3 Research in Neurodegenerative and Cardiovascular Disorders

• Neuroprotection: Fisetin has shown significant promise as a neuroprotective agent in various preclinical models of neurological disorders. Its ability to cross the blood-brain barrier allows it to exert its antioxidant and anti-inflammatory effects directly within the central nervous system.[2] This has led to its investigation as a potential therapeutic for neurodegenerative conditions like Alzheimer's and Parkinson's disease, where oxidative stress and neuroinflammation are key pathological features.[21]
• Cardiovascular Health: Preclinical studies indicate that Fisetin may confer cardiovascular benefits. It has been shown to protect cardiac tissue from oxidative stress, improve the function of vascular endothelial cells, and, in an animal model, significantly reduce the risk of atrial fibrillation following a heart attack.[7]

5.4 Analysis of Human Clinical Trials: Design, Endpoints, and Current Status

The recent development of bioavailability-enhanced formulations has catalyzed the initiation of human clinical trials. These trials represent a highly strategic and scientifically rigorous approach to translating Fisetin's preclinical promise. Rather than pursuing a broad and difficult-to-prove "anti-aging" claim, researchers are targeting specific, well-defined clinical conditions where cellular senescence is a known pathological driver. This approach allows for the testing of a clear biological hypothesis within a context that has measurable clinical endpoints. Success in these trials would not only provide a potential new therapeutic for the condition being studied but would also serve as a powerful proof-of-concept for the entire senolytic strategy in humans. The current clinical trial landscape, summarized in Table 3, is focused on areas such as frailty, post-chemotherapy recovery, and vascular aging.

Trial ID	Status (as of latest update)	Condition(s) Studied	Intervention and Dosing	Primary Outcome(s)	Sponsor
NCT03430037	Completed (April 2020)	Frailty, Inflammation in Older Women	Fisetin (Dose not specified)	Change in Frailty Index, SASP biomarkers	Mayo Clinic
NCT05595499	Recruiting	Physical Function in Stage I-III Breast Cancer Survivors	Fisetin vs. Placebo (Dose not specified); PO on days 1-3, repeated every 2 weeks for 8 weeks	6-minute walk distance (6MWD)	Jonsson Comprehensive Cancer Center
NCT06113016	Recruiting	Frailty Prevention in Breast Cancer Survivors	Fisetin and/or Exercise vs. Placebo; PO on days 1-3 of each 14-day cycle for 8 cycles	6-minute walk distance (6MWD)	Jonsson Comprehensive Cancer Center
NCT06133634	Recruiting	Vascular Function in Older Adults (≥65 years)	Fisetin (2 mg/kg/day) vs. Placebo; Intermittent 3-day dosing periods	Change in endothelial function (FMD)	University of Colorado, Boulder
NCT06399809	Recruiting	Mobility Impairment in Peripheral Artery Disease (PAD)	Fisetin vs. Placebo	Change in senescent cell abundance, 6-minute walk distance	Northwestern University
NCT07195318	Not yet recruiting	Healthy Aging in Middle-Aged and Older Adults	Fisetin (100 mg/day) vs. Placebo; Daily for 7 weeks	Safety, measures of inflammation and senescence	Ove Andersen

Table based on data from.[1] Status and details are subject to change.

These trials are designed to answer critical questions about Fisetin's efficacy and safety in humans. They employ robust designs (randomized, double-blind, placebo-controlled) and utilize both functional outcomes (e.g., 6-minute walk distance) and biological endpoints (e.g., circulating SASP factors) to assess its effects. The dosing strategies being tested vary, reflecting the ongoing debate about whether a continuous low-dose or an intermittent high-dose "hit-and-run" approach is optimal for senolytic therapy.[27] The results of these trials will be pivotal in determining the future clinical trajectory of Fisetin.

Section 6: Safety, Tolerability, and Drug Interactions

The safety profile of Fisetin is a critical consideration, particularly as it transitions from a low-dose dietary component to a high-dose, pharmacologically active supplement. While generally well-tolerated, its potential for adverse effects and significant drug-drug interactions, especially with bioavailability-enhanced formulations, warrants careful evaluation.

6.1 Human and Animal Toxicology Data

In preclinical animal studies, Fisetin has demonstrated a favorable safety profile, with a lack of observed adverse effects even when administered at very high doses.[30] However, the body of long-term human safety data, especially at the high concentrations achieved with newer formulations, remains limited.[37]

6.2 Observed Side Effects and General Tolerability in Human Use

Based on its use as a dietary supplement, Fisetin is generally considered to be well-tolerated by most individuals.[22] The most commonly reported adverse effects are mild and related to the gastrointestinal system. These can include:

• Gastrointestinal Discomfort: Some users may experience stomach pain, nausea, or diarrhea. These effects are more likely to occur at higher doses or when the supplement is taken on an empty stomach and can often be mitigated by taking Fisetin with food.[44]
• Allergic Reactions: As with any plant-derived compound, there is a potential for allergic reactions in susceptible individuals, which could manifest as skin rashes, itching, or respiratory symptoms.[44]
• Other Potential Concerns: Although less well-documented, there are theoretical concerns regarding potential hormonal effects due to Fisetin's estrogenic activity, and the possibility of liver stress with long-term, high-dose use. Individuals with pre-existing hormonal or liver conditions are advised to exercise caution.[44]

6.3 Clinically Significant Drug Interactions: A Focus on Cytochrome P450 Enzyme Inhibition

The most significant safety concern for Fisetin is its potential to interact with pharmaceutical drugs by inhibiting the Cytochrome P450 (CYP) enzyme system. The CYP enzymes, located primarily in the liver and gut wall, are responsible for the metabolism of a vast number of medications. Inhibition of these enzymes can slow the breakdown of a co-administered drug, leading to dangerously elevated plasma concentrations and an increased risk of toxicity.

Fisetin exhibits a specific and nuanced pattern of CYP enzyme inhibition. While many drug interaction concerns focus on the CYP3A4 isoenzyme, which metabolizes approximately 50% of all clinical drugs, Fisetin's effect on this enzyme is weak.[45] Instead, its inhibitory activity is much more potent against other, equally important CYP isoenzymes. This creates a specific risk profile that can be easily overlooked if one only considers CYP3A4. The primary risk is concentrated in drugs metabolized by CYP2C8 and CYP2C9. For example, the widely used anticoagulant warfarin is a classic CYP2C9 substrate. Co-administration with a potent CYP2C9 inhibitor like Fisetin could dramatically increase warfarin levels, leading to an elevated risk of severe and life-threatening bleeding. Similarly, many non-steroidal anti-inflammatory drugs (NSAIDs) and certain oral anti-diabetic medications (e.g., repaglinide) are substrates for CYP2C8 or CYP2C9. Combining these with Fisetin could lead to adverse events. This specific interaction profile represents a significant potential danger for consumers using Fisetin supplements without medical supervision, especially those on complex medication regimens.

CYP Isoenzyme	Inhibitory Effect of Fisetin	Type of Inhibition	Potential Clinical Significance	Key Sources
CYP2C8	Selective Inhibition ()	Non-competitive	May increase levels of drugs like repaglinide (anti-diabetic) and paclitaxel (chemotherapy).	47
CYP2C9	Potent Inhibition	Not specified	High risk of increasing levels of warfarin (anticoagulant), phenytoin (anti-seizure), and some NSAIDs.	45
CYP1A2	Potent Inhibition	Not specified	May increase levels of caffeine, theophylline, and clozapine.	45
CYP2C19	Potent Inhibition	Not specified	May increase levels of proton pump inhibitors (e.g., omeprazole) and clopidogrel (prodrug).	45
CYP2D6	Moderate Inhibition	Not specified	Potential to affect metabolism of many antidepressants, beta-blockers, and opioids.	45
CYP3A4	Weak Inhibition	Not specified	Lower risk of interaction compared to other isoforms, but still possible with sensitive substrates.	45
CYP1B1	Inhibition	Mixed	May inhibit the formation of carcinogenic estrogen metabolites; potentially beneficial.	48

In addition to CYP inhibition, Fisetin may potentiate the effects of anticoagulant and anti-platelet drugs through other mechanisms, further increasing bleeding risk.[44] Given this complex interaction profile, consultation with a healthcare professional is imperative before initiating Fisetin supplementation, particularly for individuals taking any prescription medications.

Section 7: Regulatory Landscape and Commercialization

The regulatory status and commercial availability of Fisetin differ significantly between major markets like the United States and the European Union, reflecting different philosophical and legal approaches to the regulation of natural products and dietary supplements.

7.1 Regulatory Status in the United States (FDA)

In the United States, Fisetin is regulated by the Food and Drug Administration (FDA) under the framework of the Dietary Supplement Health and Education Act of 1994 (DSHEA).[50] Under DSHEA, products like Fisetin are classified and regulated as food, not as drugs.[51] This means that manufacturers do not need to seek pre-market approval from the FDA or provide evidence of efficacy before selling their products. Instead, the manufacturer is solely responsible for ensuring the safety and proper labeling of their supplement.[50] The FDA's authority is primarily post-market, allowing it to take action against adulterated or misbranded products only after they are on the market.

• GRAS (Generally Recognized as Safe) Status: The GRAS designation is a regulatory status for food ingredients. A substance can be GRAS if there is a consensus among qualified experts that it is safe for its intended use. Fisetin, as a general ingredient, is not listed in the FDA's GRAS notice inventory and has not been officially recognized by the FDA as GRAS.[37] However, the regulatory landscape is evolving. In a significant development, a specific, branded Fisetin ingredient, BeFisetin®, achieved Self-Affirmed GRAS (SA-GRAS) status in April 2025.[11] This process involves a company conducting its own comprehensive safety review and having it validated by an independent panel of experts. This achievement marks a strategic shift in the Fisetin market, moving from the sale of an unregulated commodity chemical to a premium, safety-vetted ingredient. This move is likely a response to market demands for higher quality and purity, especially given reports of significant quality inconsistencies and impurities in generic Fisetin products.[11] The SA-GRAS certification provides a powerful marketing tool for differentiation and a layer of regulatory assurance for large brands looking to incorporate Fisetin into their product lines.

7.2 Regulatory Status in the European Union (EFSA)

The regulatory environment in the European Union is substantially stricter. Any food or food ingredient that was not consumed to a significant degree within the EU before May 15, 1997, is considered a "Novel Food" under Regulation (EU) 2015/2283.[53] All novel foods require a rigorous pre-market safety assessment by the European Food Safety Authority (EFSA) and formal authorization from the European Commission before they can be legally placed on the market.

Fisetin's status under this regulation is ambiguous. The provided documentation does not show any record of a Novel Food application being submitted, reviewed, or approved for Fisetin.[57] Therefore, its legal status for sale as a food supplement across the EU is unclear and may be subject to the interpretation of individual member states. It is highly probable that purified Fisetin extracts, and especially the new bioavailability-enhanced formulations, would be classified as novel foods requiring full authorization due to their lack of significant consumption history and the significant metabolic changes they induce.[59]

7.3 Market Analysis: Fisetin as a Dietary Supplement and Common Formulations

Despite the regulatory ambiguities, Fisetin is widely available for purchase as a dietary supplement, particularly in the U.S. market. It is typically marketed with claims related to healthy aging, cellular rejuvenation, cognitive support, and antioxidant protection.[17]

• Common Dosages: The dosages offered in commercial supplements vary widely, reflecting the different potential uses.
• Daily Support: For general antioxidant and anti-inflammatory support, daily doses typically range from 100 mg to 500 mg.[22]
• Senolytic Protocols: For its use as a senolytic, consumers often follow intermittent "pulse" or "hit-and-run" dosing schedules. This involves taking a much higher dose, such as 1,000 mg to 1,500 mg (often calculated as 20 mg per kg of body weight), for two or three consecutive days, followed by a rest period of several weeks or a month.[23]
• Formulations: The market features a variety of formulations designed to address Fisetin's primary challenge of poor bioavailability.
• Enhanced Bioavailability: Leading products often feature Fisetin in liposomal forms or combined with fenugreek galactomannans (e.g., Life Extension's Bio-Fisetin) to improve absorption.[23]
• Synergistic Blends: Some supplements combine Fisetin with other flavonoids, particularly the structurally similar quercetin, with the aim of achieving synergistic effects. Others include bioavailability enhancers like piperine (black pepper extract).[23]

Section 8: Synthesis, Future Directions, and Expert Recommendations

Fisetin stands at a critical juncture between profound preclinical promise and the need for rigorous clinical validation. Its journey from a simple plant pigment to a leading candidate in geroscience and senolytic therapy is a testament to its potent and multifaceted biological activity. However, its future as a therapeutic agent hinges on addressing key knowledge gaps and navigating a complex scientific and regulatory path.

8.1 Synthesis of Evidence: Reconciling Preclinical Promise with Clinical Reality

The existing body of evidence presents a clear dichotomy. On one hand, preclinical studies have established Fisetin as a remarkable molecule. Its ability to selectively clear senescent cells and subsequently extend lifespan in animal models is one of the most compelling findings in the field of anti-aging research.[4] Its potent anti-inflammatory, antioxidant, and anti-cancer effects are well-documented at a mechanistic level, providing a strong scientific rationale for its potential health benefits.[3]

On the other hand, this preclinical success has yet to be translated into proven clinical reality. The historical barrier of extremely poor bioavailability has rendered much of the early research difficult to apply to humans. While this challenge is now being overcome with advanced formulations, the human clinical trial data required to substantiate the claims made in animal models is still in its infancy. The current state is one of high potential backed by a strong scientific hypothesis, but lacking the definitive human evidence required for clinical endorsement.

8.2 Gaps in Current Knowledge and Future Research Imperatives

To advance Fisetin from a promising supplement to a validated therapeutic agent, several critical knowledge gaps must be addressed through focused research.

• Long-Term Human Safety: The most pressing need is for data on the long-term safety of Fisetin in humans, especially for the high-dose, intermittent senolytic protocols and the new high-bioavailability formulations. The potential for chronic toxicity or unforeseen adverse effects with sustained, high-level exposure is unknown.
• Optimal Dosing and Regimen: The ideal dosing strategy for Fisetin is a major unanswered question. It is unclear whether a continuous, low-dose regimen for antioxidant and anti-inflammatory support is superior to a high-dose, intermittent "hit-and-run" approach for senolytic effects. Clinical trials directly comparing these regimens for different indications are needed.
• Confirmation of Human Efficacy: The ultimate hurdle is demonstrating efficacy in well-designed, large-scale, placebo-controlled human clinical trials. It is essential to confirm that the functional improvements and lifespan extension seen in mice translate into tangible clinical benefits for humans, such as reduced frailty, improved physical function, or delayed onset of age-related diseases.
• Biomarker Development: A significant challenge in senolytic research is the lack of validated, non-invasive biomarkers to measure the burden of senescent cells in humans. The development of reliable biomarkers (e.g., specific SASP factors in the blood) is crucial for confirming that Fisetin is having its intended biological effect in clinical trials and for guiding personalized dosing.

8.3 Expert Recommendations for Research, Development, and Clinical Investigation

Based on the comprehensive analysis of the current evidence, the following strategic recommendations are proposed for the future development of Fisetin:

1. Prioritize Clinical Safety and Pharmacokinetic Studies: The immediate priority should be on conducting rigorous Phase I clinical trials. These studies must thoroughly characterize the pharmacokinetics, safety, and tolerability of the new, high-bioavailability Fisetin formulations. Dose-escalation studies are needed to define the maximum tolerated dose and establish a safe therapeutic window in humans.
2. Conduct Dedicated Drug-Drug Interaction Studies: Given Fisetin's well-documented and potent inhibitory effects on key Cytochrome P450 enzymes (particularly CYP2C8 and CYP2C9), dedicated clinical drug-drug interaction studies are not just recommended; they are imperative. These studies should investigate the effects of Fisetin on the pharmacokinetics of widely used drugs that are substrates for these enzymes (e.g., warfarin, certain anti-diabetic agents) to prevent potentially severe adverse events.
3. Maintain Strategic Focus in Clinical Efficacy Trials: Future Phase II and III trials should continue the current strategic approach of targeting specific patient populations where cellular senescence is a known and measurable contributor to pathology (e.g., post-chemotherapy frailty, chronic kidney disease, idiopathic pulmonary fibrosis). This targeted approach, which focuses on functional and biomarker-based endpoints, has a much higher probability of success than broad, ill-defined "anti-aging" trials.
4. Invest in Formulation and Manufacturing Excellence: Continued innovation in formulation science is critical to developing a Fisetin product that is not only highly bioavailable but also safe, stable, and manufacturable at scale with consistent quality. The recent achievement of SA-GRAS status by a commercial supplier is a positive step in this direction, and such standards for purity and safety should be adopted industry-wide.

In conclusion, Fisetin is a molecule of exceptional scientific interest. Its path forward requires a disciplined, pharmacologically rigorous approach that prioritizes safety, confirms mechanism of action in humans, and systematically validates its promising preclinical benefits in well-designed clinical trials.

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