Description: <b>Myricetin</b> (MYR; 3,3′,4′,5,5′,7-hexahydroxyflavone) is a dietary flavonol polyphenol abundant in berries, tea, red wine, and some medicinal plants. Its dominant biology is redox-active modulation with context-dependent pro-oxidant capacity, ranking conceptually as: <br>
(1) ROS modulation (scavenging at low dose; pro-oxidant at higher dose or with metal redox cycling), <br>
(2) PI3K/Akt/mTOR and MAPK pathway inhibition, <br>
(3) NF-κB suppression and inflammatory signaling control, and <br>
(4) mitochondrial apoptosis induction (caspase activation, ΔΨm disruption). <br>
Bioavailability is limited by low aqueous solubility and rapid conjugation (glucuronidation/sulfation); reported human plasma levels after dietary exposure are typically sub-micromolar (<1 µM), while many in-vitro cancer studies use 10–100 µM, often exceeding realistic systemic exposure. Clinical evidence remains preclinical-dominant; no robust RCT-grade anticancer efficacy established. Redox duality implies potential chemo-sensitization in oxidative tumors but also theoretical protection of normal tissue.<br>
<br>
-Possible inhibitory effects on mammalian TrxRs (thioredoxin reductase)<br>
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<h3>Myricetin (MYR) — Cancer-Relevant Pathway Effects</h3>
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells (↑/↓/↔ + qualifiers)</th>
<th>Normal Cells (↑/↓/↔ + qualifiers)</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>ROS Modulation</td>
<td>↑ ROS (high conc., pro-oxidant); ↓ ROS (low conc.)</td>
<td>↓ ROS (protective; dose-dependent)</td>
<td>P–R</td>
<td>Redox stress induction or buffering</td>
<td>Metal-chelating flavonol; can shift to pro-oxidant under tumor oxidative stress, enabling apoptosis.</td>
</tr>
<tr>
<td>2</td>
<td>PI3K/Akt/mTOR</td>
<td>↓ Akt phosphorylation (model-dependent)</td>
<td>↔ / mild inhibition</td>
<td>R–G</td>
<td>Anti-proliferative signaling</td>
<td>Common in breast, colon, and prostate cell models; often ≥10 µM required.</td>
</tr>
<tr>
<td>3</td>
<td>MAPK (ERK/JNK/p38)</td>
<td>↓ ERK; ↑ JNK/p38 (stress-activated; context)</td>
<td>↔ / adaptive stress response</td>
<td>R</td>
<td>Pro-apoptotic signaling shift</td>
<td>Promotes apoptotic cascades via stress kinase activation.</td>
</tr>
<tr>
<td>4</td>
<td>NF-κB</td>
<td>↓ NF-κB activation</td>
<td>↓ NF-κB (anti-inflammatory)</td>
<td>R–G</td>
<td>Anti-inflammatory modulation</td>
<td>May reduce tumor-promoting inflammation.</td>
</tr>
<tr>
<td>5</td>
<td>Mitochondrial Apoptosis (Caspase / ΔΨm)</td>
<td>↑ Bax; ↓ Bcl-2; ↑ caspase-3</td>
<td>↔ / protective at low dose</td>
<td>R–G</td>
<td>Intrinsic apoptosis activation</td>
<td>Frequently observed in leukemia and solid tumor models at supra-physiologic doses.</td>
</tr>
<tr>
<td>6</td>
<td>NRF2 Axis</td>
<td>↔ / mild ↑ (context-dependent)</td>
<td>↑ NRF2 (cytoprotection)</td>
<td>R–G</td>
<td>Adaptive antioxidant response</td>
<td>Less potent NRF2 activator than electrophilic isothiocyanates.</td>
</tr>
<tr>
<td>7</td>
<td>Ca²⁺ Signaling</td>
<td>↑ intracellular Ca²⁺ (mitochondrial stress; model-dependent)</td>
<td>↔</td>
<td>R</td>
<td>Apoptosis facilitation</td>
<td>Reported in some hepatoma and leukemia models.</td>
</tr>
<tr>
<td>8</td>
<td>Ferroptosis</td>
<td>↔ / potentially ↓ (iron-chelating)</td>
<td>↔</td>
<td>—</td>
<td>Lipid peroxidation modulation</td>
<td>Chelation may counter ferroptosis unless combined with pro-oxidant triggers.</td>
</tr>
<tr>
<td>9</td>
<td>Clinical Translation Constraint</td>
<td colspan="2">Low oral bioavailability; plasma <1 µM; most anticancer studies use 10–100 µM</td>
<td>—</td>
<td>PK limitation</td>
<td>Conjugation and rapid metabolism limit systemic tumor exposure.</td>
</tr>
</table>
<div><b>TSF Legend:</b> P: 0–30 min R: 30 min–3 hr G: >3 hr</div>