Description: <p><b>Hydroxytyrosol (HT; 3,4-dihydroxyphenylethanol)</b> = phenolic compound from extra-virgin olive oil (EVOO) and olives; also formed from oleuropein metabolism. Small, water-soluble catechol with high antioxidant capacity.<br>
<b>Primary mechanisms (conceptual rank):</b><br>
1) Direct ROS scavenging + lipid peroxidation inhibition (membrane protection).<br>
2) NRF2 activation → endogenous antioxidant enzymes (HO-1, NQO1, GCLC).<br>
3) Anti-inflammatory modulation (↓ NF-κB, ↓ COX-2, ↓ iNOS).<br>
4) Mitochondrial protection / biogenesis support (model-dependent; PGC-1α linkage reported).<br>
5) Anti-proliferative / pro-apoptotic signaling in cancer (dose- and model-dependent).<br>
<b>PK / bioavailability:</b> well absorbed; rapid phase II metabolism (glucuronide/sulfate conjugates); short plasma half-life; free aglycone concentrations modest vs many in-vitro studies.<br>
<b>In-vitro vs systemic exposure:</b> many cell studies use ≥10–100 µM; typical dietary/EVOO intake yields lower transient plasma levels (conjugated forms predominate).<br>
<b>Clinical evidence status:</b> strongest data in cardiometabolic/vascular endpoints; oncology evidence largely preclinical; neuroprotection mechanistically plausible with limited RCT data.</p>
<b>Hydroxytyrosol <b> is mostly only available from olive oil and leaves, but is available as a common supplement.<br>
Hydroxytyrosol & oleuropein show the most consistent direct anti-CSC activity in multiple models (breast, colon, prostate).<br>
<pre>
Hydroxytyrosol is potent against CSC phenotypes.
Mechanisms:
-Blocks EMT, reducing transition into CSC-like states
-Inhibits Notch signaling
-Reduces CD44+ / CD24– CSC markers
-Inhibits hypoxia-driven stemness (HIF-1α suppression)
Hydroxytyrosol is especially active in:
-Breast CSCs
-Melanoma CSC-like cells
-Gastric CSC models
</pre>
<h3>Hydroxytyrosol (HT) — Cancer-Relevant Pathways</h3>
<table>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>ROS tone / lipid peroxidation</td>
<td>↓ (low–mod dose); ↑ (high concentration only)</td>
<td>↓</td>
<td>P→R</td>
<td>Antioxidant; membrane protection</td>
<td>Catechol scavenger; at higher concentrations may induce pro-oxidant stress in tumors (model-dependent).</td>
</tr>
<tr>
<td>2</td>
<td>NRF2 axis</td>
<td>↑ (context-dependent)</td>
<td>↑</td>
<td>R→G</td>
<td>Endogenous antioxidant induction</td>
<td>↑ HO-1/NQO1; protective in normal tissues; could support tumor stress resistance (context-dependent).</td>
</tr>
<tr>
<td>3</td>
<td>NF-κB / COX-2 inflammation</td>
<td>↓</td>
<td>↓</td>
<td>R→G</td>
<td>Anti-inflammatory</td>
<td>Reduces pro-tumor inflammatory signaling; consistent with Mediterranean diet data.</td>
</tr>
<tr>
<td>4</td>
<td>Mitochondrial function</td>
<td>↔ / ↓ proliferation (model-dependent)</td>
<td>↑ (protective)</td>
<td>R→G</td>
<td>Bioenergetic stabilization</td>
<td>Reported support of mitochondrial integrity in normal cells; may impair cancer cell proliferation via metabolic stress.</td>
</tr>
<tr>
<td>5</td>
<td>Apoptosis (caspase activation)</td>
<td>↑ (high concentration only)</td>
<td>↔ / ↓</td>
<td>R→G</td>
<td>Pro-apoptotic in select tumors</td>
<td>Observed at supra-physiologic exposures in vitro.</td>
</tr>
<tr>
<td>6</td>
<td>Ferroptosis axis</td>
<td>↓ (anti-lipid-ROS bias)</td>
<td>↓</td>
<td>P→R</td>
<td>Inhibits lipid oxidation</td>
<td>Strong antioxidant property may counter ferroptotic strategies (context-dependent).</td>
</tr>
<tr>
<td>7</td>
<td>Clinical Translation Constraint</td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>Exposure limitations</td>
<td>Rapid metabolism; plasma free HT lower than many in-vitro doses; best considered dietary adjunct.</td>
</tr>
</table>
<p><b>TSF Legend:</b> P: 0–30 min | R: 30 min–3 hr | G: >3 hr</p>
<h3>Hydroxytyrosol (HT) — Cancer Stemness / EMT Axis (Addendum)</h3>
<table>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>EMT (Epithelial–Mesenchymal Transition)</td>
<td>↓ (model-/dose-dependent)</td>
<td>↔</td>
<td>R→G</td>
<td>Reduces EMT-associated transcription (e.g., Snail, Twist)</td>
<td>Reported attenuation of mesenchymal phenotype; relevance strongest in breast and melanoma models; mostly in-vitro.</td>
</tr>
<tr>
<td>2</td>
<td>CSC markers (CD44<sup>+</sup>/CD24<sup>–</sup>)</td>
<td>↓ (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Reduces stemness-associated phenotype</td>
<td>Observed reduction in CSC-like populations in breast cancer models; requires supra-physiologic exposure in many studies.</td>
</tr>
<tr>
<td>3</td>
<td>Notch signaling</td>
<td>↓ (model-dependent)</td>
<td>↔</td>
<td>R→G</td>
<td>Stemness pathway inhibition</td>
<td>Downregulation of Notch pathway components reported; central to CSC maintenance; not universally replicated across tumor types.</td>
</tr>
<tr>
<td>4</td>
<td>HIF-1α / hypoxia-driven stemness</td>
<td>↓ (preclinical)</td>
<td>↔</td>
<td>R→G</td>
<td>Suppresses hypoxia adaptation</td>
<td>Reduced HIF-1α signaling may attenuate hypoxia-induced CSC traits; data strongest in gastric and breast models.</td>
</tr>
<tr>
<td>5</td>
<td>Tumor-type specificity</td>
<td>Breast, Melanoma, Gastric (preclinical)</td>
<td>—</td>
<td>—</td>
<td>CSC-like cell sensitivity</td>
<td>Evidence largely limited to cell-line and xenograft systems; translational dosing gap remains significant.</td>
</tr>
</table>
<p><b>TSF Legend:</b> P: 0–30 min | R: 30 min–3 hr | G: >3 hr</p>
<br>
<h3>Hydroxytyrosol (HT) — Alzheimer’s Disease–Relevant Axes</h3>
<table>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cells (neurons/glia)</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Lipid peroxidation / neuronal membrane protection</td>
<td>↓</td>
<td>P</td>
<td>Neuroprotective antioxidant</td>
<td>Protects against oxidative membrane injury; aligns with AD oxidative stress hypothesis.</td>
</tr>
<tr>
<td>2</td>
<td>NRF2 activation</td>
<td>↑</td>
<td>R→G</td>
<td>Endogenous antioxidant upregulation</td>
<td>Supports neuronal resilience under oxidative stress.</td>
</tr>
<tr>
<td>3</td>
<td>Neuroinflammation (NF-κB)</td>
<td>↓</td>
<td>R→G</td>
<td>Microglial modulation</td>
<td>Reduces pro-inflammatory cytokines in models.</td>
</tr>
<tr>
<td>4</td>
<td>Mitochondrial integrity</td>
<td>↑</td>
<td>R→G</td>
<td>Bioenergetic stabilization</td>
<td>Improves mitochondrial function in neuronal models; may reduce apoptotic susceptibility.</td>
</tr>
<tr>
<td>5</td>
<td>Aβ toxicity modulation</td>
<td>↓ (preclinical)</td>
<td>G</td>
<td>Reduces amyloid-induced oxidative injury</td>
<td>Animal/cell evidence; limited direct human AD trials.</td>
</tr>
<tr>
<td>6</td>
<td>Clinical Translation Constraint</td>
<td>—</td>
<td>—</td>
<td>Dietary-level evidence</td>
<td>Human data strongest for Mediterranean diet patterns; isolated HT supplementation lacks large AD RCTs.</td>
</tr>
</table>
<p><b>TSF Legend:</b> P: 0–30 min | R: 30 min–3 hr | G: >3 hr</p>