tbResList Print — Uro Urolithin

Description: <b>Urolithins</b> are gut microbiota–derived dibenzopyran-6-one metabolites formed from ellagitannins → ellagic acid. They are the bioactive, systemically relevant forms responsible for most of the anticancer, mitochondrial, and signaling effects attributed to pomegranate and berry consumption.<br>

Ellagic acid itself is largely confined to the gut lumen; urolithins are what reach circulation and tissues.<br>
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Urolithin A (UA), Most studied; mitophagy, anticancer, anti-inflammatory<br>
<pre>
Humans fall into urolithin metabotypes:
Metabotype Description Approx. Population
A Produces UA (best profile) ~40%
B Produces UB ± UA ~25–30%
0 Non-producer ~30%

ROS Modulation (Context-Dependent)
Cancer cells:
-Mild ROS ↑ or redox stress → apoptosis, growth arrest
Normal cells:
-ROS ↓, improved mitochondrial efficiency

This duality is why urolithins are less chemo-antagonistic than classic antioxidants.

Anticancer Signaling
↓ PI3K/AKT/mTOR
↓ Wnt/β-catenin
↓ NF-κB, STAT3
Cell-cycle arrest (G1/S)

Unlike sulforaphane or NAC, urolithins:
-Do not strongly upregulate NRF2 in cancer cells
-May normalize NRF2 signaling in normal cells
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Direct Urolithin A Supplements: Bypass microbiome dependency<br>
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Urolithin A–type activity — Cancer vs Normal Cell Effects
<table>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>Label</th>
<th>Primary Interpretation</th>
<th>Notes</th>
</tr>

<tr>
<td>1</td>
<td>Mitophagy / mitochondrial quality control (PINK1–Parkin axis)</td>
<td>↑ mitophagy → loss of mitochondrial reserve</td>
<td>↑ mitophagy → improved mitochondrial fitness</td>
<td>Driver</td>
<td>Mitochondrial pruning and quality enforcement</td>
<td>Urolithins selectively stress cancer cells by removing dysfunctional mitochondria while rejuvenating normal-cell mitochondrial pools</td>
</tr>

<tr>
<td>2</td>
<td>Mitochondrial metabolism / bioenergetics</td>
<td>↓ metabolic flexibility; ↓ ATP resilience</td>
<td>↑ oxidative efficiency</td>
<td>Driver</td>
<td>Energy stress vs optimization</td>
<td>Cancer cells are less able to compensate for enforced mitochondrial turnover</td>
</tr>

<tr>
<td>3</td>
<td>Reactive oxygen species (ROS)</td>
<td>↑ ROS (secondary to mitochondrial stress)</td>
<td>↓ ROS</td>
<td>Secondary</td>
<td>Metabolism-linked redox shift</td>
<td>ROS changes arise from altered mitochondrial populations, not direct redox cycling</td>
</tr>

<tr>
<td>4</td>
<td>AMPK / mTOR nutrient-sensing axis</td>
<td>↑ AMPK; ↓ mTOR signaling</td>
<td>↑ AMPK (adaptive)</td>
<td>Secondary</td>
<td>Catabolic pressure and growth restraint</td>
<td>Energy-sensing pathways reinforce growth suppression in metabolically stressed tumor cells</td>
</tr>

<tr>
<td>5</td>
<td>Cell cycle regulation</td>
<td>↓ proliferation / ↑ arrest</td>
<td>↔ spared</td>
<td>Phenotypic</td>
<td>Cytostatic growth limitation</td>
<td>Growth inhibition reflects bioenergetic insufficiency rather than direct CDK inhibition</td>
</tr>

<tr>
<td>6</td>
<td>Inflammatory signaling (NF-κB / cytokines)</td>
<td>↓ pro-tumor inflammation</td>
<td>↓ inflammatory tone</td>
<td>Secondary</td>
<td>Anti-inflammatory modulation</td>
<td>Reduced inflammation contributes to chemopreventive and microenvironmental effects</td>
</tr>

<tr>
<td>7</td>
<td>NRF2 antioxidant response</td>
<td>↑ NRF2 (adaptive, secondary)</td>
<td>↑ NRF2 (protective)</td>
<td>Adaptive</td>
<td>Redox homeostasis reinforcement</td>
<td>NRF2 activation reflects improved mitochondrial quality and reduced oxidative burden rather than a cytotoxic mechanism</td>
</tr>


<tr>
<td>8</td>
<td>Apoptosis sensitivity</td>
<td>↑ sensitivity to apoptosis (stress-context dependent)</td>
<td>↓ apoptosis</td>
<td>Phenotypic</td>
<td>Threshold-dependent cell death</td>
<td>Apoptosis occurs when mitochondrial and energetic stress exceed adaptive capacity</td>
</tr>

</table>