Description: <b>Found</b> in roots, leaves, nut-hulls, bark and wood of walnut trees.<br>
Juglone (5-hydroxy-1,4-naphthoquinone) <br>
Juglans nigra refers to the black walnut tree, which is one of the most well-known sources of juglone<br>
-Research has focused on the hulls (the green outer covering of the walnut) because they have the highest concentrations.<br>
-Fresh hulls can contain juglone levels in the range of approximately 1–5% of the dry weight<br>
<br>
-Juglone can redox cycle to generate reactive oxygen species (ROS). <br>
-Increasing Bax, decreasing Bcl‑2, caspase activation, and MMP depolarization.<br>
-Modulation of MAPK pathways (including ERK, JNK, and p38) <br>
-May inhibit NF‑κB signaling<br>
-Cause DNA damage or stress that, in turn, leads to p53 pathway activation—
Pin1 Inhibition<br>
–Pin1, a peptidyl-prolyl cis/trans isomerase, is frequently overexpressed in cancer.<br>
<br>
-ic50 maybe 5-10uM<br>
-For matching 5uM, crude estimate is 5mg consumption of juglone required which might be 1.5 g of black walnut hull material<br>
<br>
<table border="1" cellspacing="0" cellpadding="4">
<tr>
<th>Rank</th>
<th>Pathway / Target Axis</th>
<th>Direction</th>
<th>Primary Effect</th>
<th>Notes / Cancer Relevance</th>
<th>Ref</th>
</tr>
<tr>
<td>1</td>
<td>Redox cycling (quinone–semiquinone system)</td>
<td>↑↑ ROS</td>
<td>Oxidative stress overload</td>
<td>Juglone can act as a redox-cycling quinone; ROS elevation is a dominant upstream driver in multiple cancer models</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC6523217/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>2</td>
<td>Thiol buffering (GSH depletion)</td>
<td>↓ GSH</td>
<td>Loss of redox buffering</td>
<td>In HL-60 leukemia cells, juglone induces ROS and explicitly depletes GSH; antioxidants block downstream apoptosis markers</td>
<td><a href="https://www.sciencedirect.com/science/article/abs/pii/S0278691512000117" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>3</td>
<td>Mitochondrial integrity (ΔΨm)</td>
<td>↓ ΔΨm</td>
<td>Mitochondrial dysfunction</td>
<td>In LNCaP prostate cancer cells, juglone decreases mitochondrial potential (ΔΨ) during intrinsic apoptosis</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC6266065/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>4</td>
<td>Intrinsic apoptosis (Caspase-9 → Caspase-3)</td>
<td>↑ Caspase-9/3 activation</td>
<td>Programmed cell death</td>
<td>Same LNCaP evidence base: intrinsic apoptosis with activation of caspases 3 and 9 is reported for juglone</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC6266065/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>5</td>
<td>DNA damage / genotoxic stress</td>
<td>↑ DNA damage</td>
<td>Checkpoint activation and death signaling</td>
<td>Juglone is reported to have genotoxic effects (DNA damage) in melanoma models, consistent with ROS-driven injury</td>
<td><a href="https://www.sciencedirect.com/science/article/abs/pii/S1065699509001607" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>6</td>
<td>p53 stress response</td>
<td>↑ p53 pathway (activation)</td>
<td>Cell-cycle arrest / apoptosis cooperation</td>
<td>Human liver cancer model: juglone drives apoptosis and autophagy via a ROS-mediated p53 pathway (in vitro and in vivo)</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/31283929/" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>7</td>
<td>MAPK stress pathways (JNK / p38)</td>
<td>↑ JNK / ↑ p38</td>
<td>Pro-death stress signaling</td>
<td>Mechanistic synthesis notes juglone induces ROS and activates JNK and p38 MAPK, contributing to cell death signaling</td>
<td><a href="https://www.sciencedirect.com/science/article/abs/pii/S0278691518302060" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>8</td>
<td>NF-κB signaling</td>
<td>↓ NF-κB</td>
<td>Reduced pro-survival transcription</td>
<td>Literature reports juglone inhibits NF-κB production/signaling in colonic cancer cell contexts (noted as prior work)</td>
<td><a href="https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.674341/full" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>9</td>
<td>PI3K–AKT survival pathway</td>
<td>↓ PI3K / ↓ p-AKT</td>
<td>Survival pathway suppression</td>
<td>NSCLC: juglone increases ROS and inhibits PI3K/Akt signaling; NAC (ROS scavenger) attenuates apoptosis and pathway changes</td>
<td><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0299921" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>10</td>
<td>Cell cycle control</td>
<td>↑ arrest</td>
<td>Proliferation blockade</td>
<td>NSCLC: juglone arrests the cell cycle alongside ROS rise and apoptosis marker changes</td>
<td><a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0299921" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>11</td>
<td>Autophagy</td>
<td>↑ autophagy (stress-associated)</td>
<td>Stress adaptation / death crosstalk</td>
<td>Juglone induces both apoptosis and autophagy in cancer cells via MAPK pathway modulation (with ROS-MAPK coupling)</td>
<td><a href="https://www.sciencedirect.com/science/article/abs/pii/S0278691518302060" target="_blank">(ref)</a></td>
</tr>
<tr>
<td>12</td>
<td>Angiogenesis signaling (VEGF)</td>
<td>↓ VEGF</td>
<td>Reduced vascular support</td>
<td>Pancreatic cancer cell lines: juglone reduces VEGF gene expression (and other metastasis/angiogenesis-related genes) at sub-IC50 exposure</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/33502882/" target="_blank">(ref)</a></td>
</tr>
</table>