Description: <b>Hyperoside</b> is a chemical compound and a quercetin galactoside. It is found in various plants and has antibacterial, antifungal and UV blocking properties.<br>
Hyperoside is an active ingredient in plants, such as Hypericum monogynum in Hypericaceae, Crataegus pinnatifida in Rosaceae and Polygonum aviculare in Polygonaceae.<br>
Hyperoside is a natural flavonol glycoside in various plants, such as Crataegus pinnatifida Bge, Forsythia suspensa, and Cuscuta chinensis Lam.<br>
**-Note NRF2 up in normal cells and down in cancer cells**<br>
-not currently available as supplement, but it is in Hawthorn Extract. (Natural factors lists it as hyperoside equilvalents 6.6mg/300mg)<br>
<p><b>Hyperoside</b> — also known as hyperin and quercetin-3-O-β-D-galactoside, is a naturally occurring flavonol glycoside consisting of quercetin conjugated at the 3-position to β-D-galactose. It is found in numerous medicinal and dietary plants including species of <i>Hypericum</i>, <i>Crataegus</i>, <i>Polygonum</i>, and <i>Rhododendron</i>. It is classified as a plant-derived flavonoid/polyphenolic small molecule. Hyperoside has antioxidant and cytoprotective activity in many normal-cell models but can produce cancer-selective stress responses, apoptosis, autophagy, and ferroptosis depending on tumor type and concentration. Its aglycone is quercetin.</p>
<p><b>Primary mechanisms (ranked):</b></p>
<ol>
<li>Apoptosis induction through mitochondrial dysfunction, Bax/Bcl-2 modulation, cytochrome-c release, and caspase-9/caspase-3 activation.</li>
<li>PI3K/AKT/mTOR suppression with autophagy induction; ATG13-mediated autophagy has recently been identified as an important mechanism in NSCLC.</li>
<li>NF-κB pathway inhibition, reducing prosurvival and inflammatory signaling and promoting apoptotic susceptibility.</li>
<li>Redox modulation with strong context dependence: hyperoside can suppress excessive ROS in breast-cancer and normal-cell models, while in other tumor contexts oxidative stress contributes to cytotoxicity.</li>
<li>NRF2/SLC7A11/GPX4 suppression and ferroptosis induction in chronic myeloid leukemia; this contrasts with NRF2 activation and antioxidant cytoprotection in many normal-cell models.</li>
<li>MAPK modulation including p38/JNK-mediated mitochondrial apoptosis and context-dependent ERK regulation.</li>
<li>Cell-cycle arrest through p53/p21 and related regulatory pathways.</li>
<li>Suppression of tumor-cell migration, invasion, EMT, and inflammatory signaling.</li>
<li>Radiosensitization through suppression of STAT3/AKT/ERK signaling demonstrated preclinically in esophageal carcinoma.</li>
</ol>
<p><b>Bioavailability / PK relevance:</b> Oral bioavailability of intact hyperoside appears poor. Rat studies found very low systemic exposure after intragastric administration, with substantially greater exposure after parenteral administration. Hyperoside is relatively resistant to gastrointestinal hydrolysis compared with isoquercitrin, which may limit absorption of its quercetin aglycone. Distribution studies indicate preferential accumulation in kidney relative to several other organs. Nanoparticle and liposomal formulations have therefore been investigated to improve delivery and tumor or mitochondrial accumulation. Long-term high-dose exposure warrants caution because renal toxicity has been reported preclinically.</p>
<p><b>In-vitro vs systemic exposure relevance:</b> Many anticancer experiments use approximately 10–100 µM hyperoside, while some autophagy studies have used 0.5–2 mM. These concentrations, particularly the millimolar experiments, are unlikely to represent achievable concentrations of unchanged hyperoside following conventional oral administration. Consequently, direct translation of many in-vitro anticancer effects to oral supplementation is weak without an exposure-enhancing formulation.</p>
<p><b>Clinical evidence status:</b> Preclinical. Anticancer activity has been demonstrated in multiple cancer-cell systems and several mouse xenograft or chemically induced tumor models, including lung, breast, pancreatic, skin, liver, colorectal, esophageal, and hematologic malignancy models. There is currently no established human anticancer efficacy, approved oncology indication, or convincing interventional clinical evidence for purified hyperoside. FDA substance registration identifies hyperoside chemically but does not constitute drug approval.</p>
<h3>Hyperoside Cancer-Relevant Mechanisms</h3>
<table>
<thead>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells</th>
<th>Normal Cells</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
</thead>
<tbody>
<tr>
<td>1</td>
<td>Mitochondrial apoptosis</td>
<td>↑ Bax/Bcl-2; ↑ cytochrome c; ↑ caspase-9; ↑ caspase-3; ↓ mitochondrial membrane potential</td>
<td>Often ↔ or cytoprotective at lower concentrations</td>
<td>Apoptotic cell death</td>
<td>Observed across lung, pancreatic and colorectal models; one of the most reproducible anticancer effects.</td>
</tr>
<tr>
<td>2</td>
<td>PI3K/AKT/mTOR signaling</td>
<td>↓ PI3K; ↓ AKT; ↓ mTOR; ↓ p70S6K; ↓ 4E-BP1</td>
<td>Context-dependent</td>
<td>↓ survival signaling; ↑ autophagy and apoptosis</td>
<td>Strongly demonstrated in NSCLC and skin-cancer models.</td>
</tr>
<tr>
<td>3</td>
<td>Autophagy and ATG13</td>
<td>↑ ATG13; ↑ LC3-II; ↑ autophagosomes</td>
<td>↔ in some comparative epithelial-cell experiments</td>
<td>Autophagy-associated tumor suppression</td>
<td>Recent NSCLC data support ATG13-mediated autophagy as an upstream contributor to apoptosis.</td>
</tr>
<tr>
<td>4</td>
<td>NF-κB inflammatory and survival signaling</td>
<td>↓ NF-κB activation; ↓ inflammatory cytokines; ↓ prosurvival signaling</td>
<td>↓ excessive inflammatory activation (context-dependent)</td>
<td>↑ apoptosis; ↓ inflammation and tumor progression</td>
<td>Repeatedly reported in lung, pancreatic and breast models.</td>
</tr>
<tr>
<td>5</td>
<td>NRF2/SLC7A11/GPX4 ferroptosis axis</td>
<td>↓ NRF2; ↓ SLC7A11; ↓ GPX4; ↑ lipid oxidative stress</td>
<td>↑ NRF2/HO-1 in oxidative-stress models</td>
<td>↑ ferroptosis</td>
<td>Important context-dependent differential effect. Direct NRF2 targeting has been reported in chronic myeloid leukemia, whereas normal cells commonly show NRF2 activation.</td>
</tr>
<tr>
<td>6</td>
<td>Redox regulation</td>
<td>↑ or ↓ ROS (context-dependent)</td>
<td>↓ excessive ROS; ↑ antioxidant defenses</td>
<td>Context-dependent oxidative stress or antioxidant protection</td>
<td>ROS direction is not uniform across cancer types. Breast-cancer studies report ↓ ROS, whereas some colorectal and ferroptotic models depend on increased oxidative stress.</td>
</tr>
<tr>
<td>7</td>
<td>p38/JNK mitochondrial stress signaling</td>
<td>↑ p38; ↑ JNK (model-dependent)</td>
<td>Context-dependent</td>
<td>↑ mitochondrial apoptosis</td>
<td>Particularly demonstrated in A549 NSCLC cells.</td>
</tr>
<tr>
<td>8</td>
<td>p53/p21 cell-cycle control</td>
<td>↑ p53; ↑ p21; ↑ G1 or G2/M arrest (model-dependent)</td>
<td>Context-dependent</td>
<td>↓ proliferation</td>
<td>Reported in colorectal and lung models; exact arrest point varies with model.</td>
</tr>
<tr>
<td>9</td>
<td>EGFR/ERK/FOXO1 signaling</td>
<td>↓ EGFR/ERK signaling; ↑ FOXO1</td>
<td>Unclear</td>
<td>↓ proliferation; ↑ apoptosis</td>
<td>Recent NSCLC work identifies this axis as a potential therapeutic mechanism; T790M-positive NSCLC also shows FOXO1 upregulation.</td>
</tr>
<tr>
<td>10</td>
<td>Migration invasion and EMT</td>
<td>↓ migration; ↓ invasion; ↓ mesenchymal phenotype; ↑ E-cadherin</td>
<td>Unclear</td>
<td>↓ metastatic phenotype</td>
<td>Observed across several solid-tumor models including lung and esophageal carcinoma.</td>
</tr>
<tr>
<td>11</td>
<td>Radiosensitization</td>
<td>↑ radiation sensitivity; ↓ STAT3/AKT/ERK</td>
<td>Insufficient evidence</td>
<td>↑ radiation-induced tumor control</td>
<td>Demonstrated preclinically in esophageal carcinoma cells and mouse tumors; not clinically validated.</td>
</tr>
<tr>
<td>12</td>
<td>Clinical Translation Constraint</td>
<td>Low oral exposure</td>
<td>Potential renal accumulation with prolonged high-dose exposure</td>
<td>Limits systemic translation</td>
<td>Poor oral bioavailability and frequent use of high micromolar to millimolar experimental concentrations are major limitations. Targeted nanoparticles and liposomes may improve exposure.</td>
</tr>
</tbody>
</table>
<br><br>
<p><b>Hyperoside and Alzheimer's disease:</b> Hyperoside has significant preclinical neuroprotective evidence in Alzheimer's disease models. Long-term administration in APP/PS1 transgenic mice improved spatial learning and memory and reduced amyloid plaque deposition, tau phosphorylation, activated microglia and astrocytes, neuroinflammation, and oxidative stress. Mechanistic evidence implicates suppression of BACE1 and GSK-3β, protection of the blood-brain barrier, inhibition of mitochondrial and caspase-dependent apoptosis, and broader antioxidant/anti-inflammatory effects. Evidence remains preclinical; clinical efficacy in human Alzheimer's disease has not been established.</p>
<h3>Hyperoside Alzheimer's-Relevant Mechanisms</h3>
<table>
<thead>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Modulation</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
</thead>
<tbody>
<tr>
<td>1</td>
<td>Amyloid and BACE1</td>
<td>↓ BACE1; ↓ Aβ deposition</td>
<td>↓ amyloid pathology</td>
<td>Demonstrated in APP/PS1 mice following chronic treatment.</td>
</tr>
<tr>
<td>2</td>
<td>GSK-3β and tau</td>
<td>↓ GSK-3β activity/signaling; ↓ tau phosphorylation</td>
<td>↓ tau pathology</td>
<td>Provides a mechanistic connection between hyperoside treatment and reduced pathological tau phosphorylation.</td>
</tr>
<tr>
<td>3</td>
<td>Neuroinflammation</td>
<td>↓ activated microglia; ↓ activated astrocytes; ↓ inflammatory signaling</td>
<td>↓ neuroinflammation</td>
<td>Observed in chronic APP/PS1 treatment studies.</td>
</tr>
<tr>
<td>4</td>
<td>Oxidative stress and NRF2</td>
<td>↓ ROS; ↑ NRF2/HO-1 antioxidant defenses (context-dependent)</td>
<td>Neuronal protection</td>
<td>NRF2 activation is well established in non-cancer oxidative-stress models and is mechanistically consistent with hyperoside's neuroprotective phenotype.</td>
</tr>
<tr>
<td>5</td>
<td>Blood-brain barrier integrity</td>
<td>↑ ZO-1; ↑ claudin-5; ↑ occludin; ↓ MMP-2; ↓ MMP-9</td>
<td>↓ Aβ-induced BBB disruption</td>
<td>Demonstrated primarily in Aβ-exposed brain endothelial-cell models.</td>
</tr>
<tr>
<td>6</td>
<td>Mitochondrial apoptosis</td>
<td>↓ Bax/Bcl-2; ↓ cytochrome c release; ↓ caspase activation</td>
<td>↓ neuronal and endothelial apoptosis</td>
<td>Opposite therapeutic direction to its pro-apoptotic action in cancer cells.</td>
</tr>
<tr>
<td>7</td>
<td>Clinical Translation Constraint</td>
<td>Low oral bioavailability; uncertain human CNS exposure</td>
<td>Limits clinical inference</td>
<td>No established human AD efficacy; brain exposure and therapeutically relevant human dosing remain poorly defined.</td>
</tr>
</tbody>
</table>