Overview

Myricetin (3,5,7,3',4',5'-hexahydroxyflavone) is a naturally occurring flavonol belonging to the flavonoid family of polyphenolic compounds. It is found in a wide variety of fruits, vegetables, herbs, and beverages, with particularly high concentrations in bayberries (Myrica rubra, from which it derives its name), grapes, cranberries, blueberries, walnuts, and tea. Structurally, myricetin is distinguished from other common flavonols such as quercetin and kaempferol by an additional hydroxyl group on the B-ring (3',4',5'-trihydroxy pattern), giving it six total hydroxyl groups that contribute to its exceptional radical-scavenging capacity — one of the highest among dietary flavonoids.

The pharmacological activities of myricetin span multiple therapeutic domains. As an antioxidant, it directly scavenges reactive oxygen and nitrogen species, chelates transition metals (Fe2+, Cu2+) that catalyze Fenton reactions, and activates endogenous antioxidant defenses through the Nrf2/ARE pathway. Its anti-inflammatory effects are mediated through inhibition of NF-kB, suppression of COX-2 and iNOS expression, and modulation of MAPK signaling cascades. In metabolic research, myricetin has demonstrated remarkable anti-diabetic potential: it inhibits alpha-glucosidase (reducing postprandial glucose spikes), activates AMPK (enhancing glucose uptake and fatty acid oxidation), improves insulin sensitivity through insulin receptor substrate (IRS) signaling, and protects pancreatic beta cells from glucotoxicity-induced apoptosis. Animal studies have consistently shown reductions in fasting glucose, HbA1c, and insulin resistance with myricetin supplementation.

Neuroprotective research on myricetin has generated particular interest. The compound inhibits the aggregation and fibrillization of both amyloid-beta (Abeta) and tau protein in vitro, with binding affinities that make it one of the most potent natural anti-amyloid flavonoids identified. It crosses the blood-brain barrier, inhibits acetylcholinesterase (enhancing cholinergic transmission), and protects neurons against glutamate excitotoxicity and oxidative stress in cell and animal models of Alzheimer's disease. Anti-cancer research has identified myricetin as an inhibitor of PI3K, Akt, and multiple protein kinases involved in tumor proliferation and survival. Bioavailability of oral myricetin is limited (approximately 10–15%) due to extensive first-pass metabolism and glucuronidation, though this can be improved through co-administration with piperine or phospholipid complexes. Typical supplemental doses range from 100–500 mg daily, and it pairs well with other polyphenols such as resveratrol, quercetin, and fisetin in comprehensive antioxidant and longevity protocols.

Mechanism of Action

Chemical Structure & Antioxidant Capacity

Myricetin (3,5,7,3',4',5'-hexahydroxyflavone) is a flavonol found abundantly in berries, grapes, walnuts, tea, and vegetables. Its six hydroxyl groups — including the 3',4',5'-trihydroxyl (pyrogallol) arrangement on the B-ring — give it one of the highest antioxidant capacities among dietary flavonoids. The catechol/pyrogallol B-ring donates hydrogen atoms to neutralize superoxide (O₂⁻), hydroxyl (OH•), peroxyl (ROO•), and peroxynitrite (ONOO⁻) radicals. The 3-OH and 4-oxo groups chelate Fe²⁺ and Cu²⁺ ions, preventing Fenton reaction-mediated hydroxyl radical generation.

NF-kB & Inflammatory Suppression

Myricetin inhibits NF-kB activation by blocking IKK-mediated IkBα phosphorylation and preventing p65 nuclear translocation. It also suppresses upstream MAPK cascade components — p38, JNK, and ERK1/2 phosphorylation — in LPS-stimulated macrophages and microglial cells. This dual NF-kB/MAPK suppression reduces transcription of COX-2, iNOS, TNF-alpha, IL-1beta, IL-6, and MCP-1, with potency comparable to or exceeding quercetin and kaempferol in cell-based assays (PMID: 19799425).

Nrf2/ARE Pathway Activation

Myricetin activates the Nrf2/Keap1/ARE cytoprotective pathway. It modifies reactive cysteine residues on Keap1, releasing Nrf2 from proteasomal degradation. Nuclear Nrf2 binds antioxidant response elements (ARE), upregulating heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and glutamate-cysteine ligase (GCL), enhancing cellular antioxidant and detoxification capacity.

Neuroprotective Effects

In neuronal models, myricetin protects against amyloid-beta-induced toxicity by inhibiting beta-secretase (BACE1) activity and preventing amyloid fibril formation. It reduces tau hyperphosphorylation by inhibiting glycogen synthase kinase 3-beta (GSK-3β) and activating PP2A (protein phosphatase 2A). These combined anti-amyloidogenic and anti-tau effects, along with anti-neuroinflammatory activity in microglia, support neuroprotective applications.

Metabolic & Anticancer Mechanisms

Myricetin activates AMPK in hepatocytes and adipocytes, promoting fatty acid oxidation and glucose uptake while suppressing lipogenesis. In cancer cells, it inhibits the PI3K/Akt/mTOR pathway, induces G2/M cell cycle arrest via CDK1/cyclin B1 inhibition, and promotes apoptosis through mitochondrial membrane depolarization and caspase-3/9 activation.

Reconstitution Calculator

Research

Safety Profile

Myricetin is generally considered safe with a low risk of side effects, though high doses may cause mild gastrointestinal upset. It may have anti-platelet effects and should be used with caution by individuals on blood-thinning medications. Data on long-term use is limited.

Pharmacokinetic Profile