Description: <p><b>Celastrol</b> — a quinone methide triterpenoid isolated from <i>Tripterygium wilfordii</i> (Thunder God Vine). Potent redox-active and pleiotropic signaling modulator studied in oncology, inflammation, and metabolic disease.</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) Proteostasis stress induction (HSP90 inhibition; HSF1 activation)<br>
2) NF-κB suppression (IKK inhibition; anti-survival transcription blockade)<br>
3) ROS generation → mitochondrial apoptosis<br>
4) STAT3 inhibition<br>
5) PI3K/AKT/mTOR modulation (context-dependent)</p>
<p><b>Bioavailability / PK relevance:</b> Poor aqueous solubility; narrow therapeutic index; rapid metabolism; dose-limiting toxicity in systemic use. Many mechanistic studies use micromolar concentrations.</p>
<p><b>In-vitro vs oral exposure:</b> Anti-cancer cytotoxicity typically at concentrations unlikely achievable safely without advanced delivery systems (qualifier: high concentration only for direct tumor apoptosis).</p>
<p><b>Clinical evidence status:</b> Preclinical oncology; early translational investigation; no approved cancer indication.</p>
<b>Celastrol</b>—a bioactive compound extracted from traditional Chinese medicinal plants such as Tripterygium wilfordii (Thunder God Vine).<br>
<br>
Pathways:<br>
-inhibit NF-κB activation<br>
-disrupt the function of chaperone proteins like HSP90 and HSP70, which are often overexpressed in cancer cells<br>
-attenuate Akt phosphorylation and downstream mTOR signaling<br>
-modulate components of the MAPK pathway, including ERK, JNK, and p38.<br>
-increase intracellular ROS levels in cancer cells<br>
-inhibiting STAT3<br>
<br>
<h3>Celastrol — Cancer vs Normal Cell Pathway Map</h3>
<table border="1" cellpadding="4" cellspacing="0">
<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>HSP90 / Proteostasis stress</td>
<td>↓ client proteins</td>
<td>↔ / ↑ stress (dose-dependent)</td>
<td>R/G</td>
<td>Oncoprotein destabilization</td>
<td>HSP90 inhibition leads to degradation of AKT, HER2, EGFR and other client proteins.</td>
</tr>
<tr>
<td>2</td>
<td>NF-κB</td>
<td>↓ (primary)</td>
<td>↓</td>
<td>R/G</td>
<td>Reduced inflammatory and survival transcription</td>
<td>IKK inhibition suppresses NF-κB activation; central anti-survival axis.</td>
</tr>
<tr>
<td>3</td>
<td>ROS</td>
<td>↑ (primary; dose-dependent)</td>
<td>↑ (high concentration)</td>
<td>P/R</td>
<td>Oxidative stress induction</td>
<td>Quinone methide structure enables redox cycling; contributes to apoptosis.</td>
</tr>
<tr>
<td>4</td>
<td>Intrinsic apoptosis (Bax↑, Bcl-2↓, caspases)</td>
<td>↑</td>
<td>↑ (high dose)</td>
<td>R/G</td>
<td>Mitochondrial apoptosis</td>
<td>Often ROS-mediated; cancer cells more vulnerable due to baseline oxidative stress.</td>
</tr>
<tr>
<td>5</td>
<td>STAT3</td>
<td>↓</td>
<td>↔</td>
<td>R/G</td>
<td>Reduced proliferative signaling</td>
<td>Inhibits STAT3 phosphorylation in multiple tumor models.</td>
</tr>
<tr>
<td>6</td>
<td>PI3K/AKT/mTOR</td>
<td>↓ (secondary)</td>
<td>↔</td>
<td>R/G</td>
<td>Anabolic signaling suppression</td>
<td>Often downstream of HSP90 inhibition and proteotoxic stress.</td>
</tr>
<tr>
<td>7</td>
<td>NRF2</td>
<td>↑ (adaptive resistance; context-dependent)</td>
<td>↑</td>
<td>R/G</td>
<td>Stress-response activation</td>
<td>Low/moderate doses may activate NRF2; excessive ROS may overwhelm defense in tumors.</td>
</tr>
<tr>
<td>8</td>
<td>Ferroptosis</td>
<td>↑ (investigational; ROS-linked)</td>
<td>↔</td>
<td>R/G</td>
<td>Lipid peroxidation vulnerability</td>
<td>Oxidative stress environment may sensitize to ferroptotic pathways.</td>
</tr>
<tr>
<td>9</td>
<td>HIF-1α</td>
<td>↓ (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Reduced hypoxia adaptation</td>
<td>Linked to suppression of angiogenesis-related signaling.</td>
</tr>
<tr>
<td>10</td>
<td>Ca²⁺ / ER stress</td>
<td>↑ (stress-mediated)</td>
<td>↑ (high dose)</td>
<td>P/R</td>
<td>UPR activation</td>
<td>Proteostasis disruption induces ER stress response.</td>
</tr>
<tr>
<td>11</td>
<td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td>
<td>↓ (toxicity)</td>
<td>—</td>
<td>Narrow therapeutic window</td>
<td>Systemic toxicity and solubility challenges limit clinical oncology development.</td>
</tr>
</table>
<p><b>TSF legend:</b><br>
P: 0–30 min (direct redox/protein interactions)<br>
R: 30 min–3 hr (acute stress and signaling shifts)<br>
G: >3 hr (gene regulation and phenotype outcomes)</p>