tbResList Print — ISQ isoquercitrin

Description: <p><b>Isoquercitrin</b> - Quercetin-3-O-Glucoside</p>

<p><b>Alternative Names:</b> Isoquercetin, quercetin-3-O-glucoside, quercetin-3-O-β-D-glucopyranoside, Q3G, IQ</p>

<p><b>Type:</b> Flavonol glycoside / quercetin glycoside / natural phytochemical</p>

<p><b>Sources:</b> Naturally present in numerous medicinal plants, fruits, vegetables, and plant-derived foods. Isoquercitrin can also be produced from rutin by enzymatic removal of the rhamnose residue.</p>

<p><b>Function:</b> Isoquercitrin is a bioactive quercetin glycoside with antioxidant, anti-inflammatory, anticancer, metabolic, and neuroprotective effects. Reported mechanisms include modulation of Nrf2/ARE, NF-κB, JAK/STAT3, PI3K/AKT, MAPK, AMPK, Wnt signaling, oxidative stress, and programmed cell death.</p>

<p><b>Cancer:</b> Preclinical studies demonstrate inhibition of cancer-cell proliferation, survival, migration, and tumor-associated signaling together with induction of apoptosis and modulation of oxidative stress. Anticancer mechanisms include regulation of Wnt, MAPK, JAK/STAT3, PI3K/AKT, NF-κB, and related signaling pathways.</p>

<p><b>Alzheimer's Disease:</b> Preclinical studies indicate neuroprotective activity, including improved learning and memory in amyloid-β-induced models and reduction of oxidative and inflammatory neuronal injury.</p>


<p><b>Isoquercitrin</b> — also called isoquercetin, quercetin-3-O-glucoside, quercetin-3-O-β-D-glucopyranoside, Q3G, IQ, or ISQ, is a naturally occurring flavonol glycoside consisting of quercetin conjugated to glucose at the 3-O position. It is a dietary phytochemical and quercetin derivative found in many fruits, vegetables, medicinal plants, and plant-derived foods; it can also be produced from rutin by enzymatic removal of rhamnose. Isoquercitrin is generally absorbed more efficiently than quercetin aglycone or rutin, but circulating intact isoquercitrin is limited because intestinal and hepatic metabolism rapidly produces quercetin glucuronide, sulfate, methylated, and other metabolites. Enzymatically modified isoquercitrin and α-glycosyl isoquercitrin are related higher-solubility preparations but should not be treated as pharmacokinetically identical to native isoquercitrin.</p>

<p><b>Primary mechanisms (ranked):</b></p>
<ol>
<li>↓ PI3K/AKT/mTOR survival signaling and ↑ mitochondria-dependent, caspase-mediated apoptosis in several tumor models.</li>
<li>↑ AMPK signaling with ↓ mTOR/p70S6K activity, producing metabolic stress, autophagy, and apoptosis.</li>
<li>↓ canonical Wnt/β-catenin transcriptional signaling, including downstream c-Myc, cyclin D1, and survivin in Wnt-dependent tumor models.</li>
<li>↑ mitochondrial dysfunction and intrinsic apoptosis in susceptible cancer cells, including loss of mitochondrial membrane potential, ↑ Bax/Bcl-2 ratio, PARP cleavage, and caspase activation.</li>
<li>↑ ROS in selected cancer models, where oxidative stress can function upstream of AMPK activation, autophagy, and apoptosis; this is context-dependent because isoquercitrin is antioxidant in many normal-cell and disease models.</li>
<li>MAPK remodeling, typically ↓ ERK and p38 signaling with ↑ JNK in some cancer models.</li>
<li>↓ migration, invasion, and EMT-associated phenotypes in several tumor models.</li>
<li>Secondary/context-dependent modulation of JAK/STAT3, NF-κB inflammatory signaling, and NRF2/ARE antioxidant defenses.</li>
</ol>

<p><b>Bioavailability / PK relevance:</b> Oral isoquercitrin is absorbed substantially better than rutin and is rapidly processed in the intestine and liver. Human administration of quercetin-3-glucoside produces plasma quercetin-derived conjugates with peak total quercetin concentrations in the low-micromolar range; intact glucoside is essentially absent or present only in very small quantities in plasma. Therefore, systemic biological activity after oral administration is likely mediated substantially by quercetin conjugates and downstream metabolites rather than prolonged exposure to intact isoquercitrin. Enzymatic glycosylation can further improve solubility and systemic exposure, but EMIQ/AGIQ should be distinguished from native isoquercitrin.</p>

<p><b>In-vitro vs systemic exposure relevance:</b> Many anticancer experiments use approximately 20–200 µM isoquercitrin, whereas human oral exposure produces predominantly quercetin metabolites at substantially lower free/intact isoquercitrin concentrations. Consequently, direct tumor-cell effects demonstrated at tens to hundreds of micromolar intact isoquercitrin may exceed realistically achievable systemic exposure after conventional oral dosing. Lower-micromolar or metabolite-mediated effects have greater translational plausibility. The bladder is a potential special context because urinary exposure to flavonoid metabolites may differ from plasma exposure, but this has not established clinical anticancer efficacy.</p>

<p><b>Clinical evidence status:</b> Cancer: preclinical only; cell-culture and xenograft evidence exists for hepatocellular, bladder, pancreatic, colorectal, melanoma, osteosarcoma, esophageal and other tumor models, but there is no established anticancer indication or convincing human oncology trial evidence. Human studies of isoquercitrin-related preparations have primarily evaluated cardiovascular, antioxidant, exercise/nutrition, or allergic outcomes rather than cancer. Alzheimer’s disease: preclinical only, with cell and rodent evidence for anti-amyloidogenic, antioxidant, mitochondrial-protective, and cognitive effects; no established human AD efficacy. Regulatory use should not be confused with therapeutic validation: Health Canada lists isoquercitrin as an approved NHP ingredient, while α-glycosyl isoquercitrin has FDA GRAS-notice status for specified food uses; neither status represents approval as a cancer or Alzheimer treatment.</p>

<h3>Isoquercitrin Cancer-Relevant Mechanisms</h3>
<table border="1" cellpadding="4" cellspacing="0">
<thead>
<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>
</thead>
<tbody>
<tr>
<td>1</td>
<td>PI3K AKT mTOR survival signaling</td>
<td>↓ PI3K<br>↓ p-AKT<br>↓ mTOR</td>
<td>↔ / context-dependent</td>
<td>R/G</td>
<td>Reduced survival and anabolic signaling</td>
<td>One of the strongest recurring anticancer axes; demonstrated in bladder cancer and melanoma and supported by newer tumor models.</td>
</tr>
<tr>
<td>2</td>
<td>AMPK mTOR p70S6K metabolic signaling</td>
<td>↑ p-AMPK<br>↓ p-mTOR<br>↓ p70S6K</td>
<td>↑ AMPK (context-dependent)</td>
<td>R/G</td>
<td>Metabolic stress, autophagy, and apoptosis</td>
<td>Strong evidence in hepatocellular and bladder cancer models. AMPK activation can be metabolically protective in normal tissue but cytotoxic under tumor stress conditions.</td>
</tr>
<tr>
<td>3</td>
<td>Wnt β-catenin transcription</td>
<td>↓ Wnt transcription<br>↓ c-Myc<br>↓ Cyclin D1<br>↓ Survivin</td>
<td>↔ / model-dependent</td>
<td>R/G</td>
<td>Reduced proliferation and survival</td>
<td>Direct functional inhibition of canonical Wnt signaling has been demonstrated in colorectal cancer. Osteosarcoma studies also implicate β-catenin suppression. Direction is tissue-dependent outside cancer.</td>
</tr>
<tr>
<td>4</td>
<td>Mitochondrial apoptosis</td>
<td>↑ Bax/Bcl-2 ratio<br>↓ mitochondrial membrane potential<br>↑ caspase-9<br>↑ caspase-3<br>↑ PARP cleavage</td>
<td>↔ / ↓ apoptosis under oxidative injury</td>
<td>R/G</td>
<td>Intrinsic programmed cell death</td>
<td>Frequently observed tumor phenotype. Selectivity is model-dependent; isoquercitrin can instead protect normal cells from mitochondrial oxidative injury.</td>
</tr>
<tr>
<td>5</td>
<td>Autophagy</td>
<td>↑ (excessive or pro-death; model-dependent)</td>
<td>↑ / ↔ (stress-dependent)</td>
<td>R/G</td>
<td>Autophagic stress contributing to apoptosis</td>
<td>In HCC, autophagy inhibition reduces isoquercitrin-induced apoptosis, supporting a functional pro-death role. Similar excessive autophagy is reported in ESCC.</td>
</tr>
<tr>
<td>6</td>
<td>Reactive oxygen species stress</td>
<td>↑ (context-dependent)</td>
<td>↓ (commonly antioxidant)</td>
<td>P/R</td>
<td>Redox-mediated tumor stress</td>
<td>In T24 bladder cancer cells ROS rises upstream of AMPK and apoptosis. In normal or oxidatively injured cells isoquercitrin commonly lowers ROS, indicating potentially useful redox selectivity but not a universal tumor-specific mechanism.</td>
</tr>
<tr>
<td>7</td>
<td>MAPK ERK JNK p38 signaling</td>
<td>↓ ERK<br>↓ p38<br>↑ JNK (model-dependent)</td>
<td>↓ stress MAPK activation in injury models</td>
<td>R/G</td>
<td>Growth suppression and apoptotic signaling</td>
<td>Reported in liver and pancreatic cancer models. Direction is stimulus- and tissue-dependent, particularly in normal cells.</td>
</tr>
<tr>
<td>8</td>
<td>Cell cycle progression</td>
<td>↓ proliferation<br>↑ G1 or sub-G1 arrest</td>
<td>↔ at lower exposures</td>
<td>G</td>
<td>Growth arrest</td>
<td>G1 arrest is reported in liver, pancreatic, and bladder models; sub-G1 accumulation accompanies apoptosis in melanoma.</td>
</tr>
<tr>
<td>9</td>
<td>Migration invasion and EMT</td>
<td>↓ migration<br>↓ invasion<br>↓ mesenchymal phenotype</td>
<td>↔</td>
<td>G</td>
<td>Reduced metastatic phenotype</td>
<td>Observed in osteosarcoma and esophageal cancer models and linked partly to Wnt and AKT/mTOR suppression.</td>
</tr>
<tr>
<td>10</td>
<td>JAK STAT3 signaling</td>
<td>↓ STAT3 (model-dependent)</td>
<td>↓ JAK2 STAT3 during inflammatory injury</td>
<td>R/G</td>
<td>Reduced survival and inflammatory transcription</td>
<td>Evidence exists in bladder cancer and non-cancer inflammatory models, but this is less consistently established than PI3K/AKT, AMPK, or Wnt signaling.</td>
</tr>
<tr>
<td>11</td>
<td>NF-κB inflammatory signaling</td>
<td>↓ (context-dependent)</td>
<td>↓ inflammatory activation</td>
<td>R/G</td>
<td>Anti-inflammatory signaling</td>
<td>Supported broadly in isoquercitrin pharmacology but is better established as an anti-inflammatory mechanism than as a primary tumor-killing mechanism.</td>
</tr>
<tr>
<td>12</td>
<td>NRF2 ARE antioxidant response</td>
<td>↑ / context-dependent</td>
<td>↑ NRF2 antioxidant defense</td>
<td>R/G</td>
<td>Secondary cytoprotective redox regulation</td>
<td>Important in normal-tissue protection and oxidative-stress models. NRF2 activation can theoretically protect malignant cells, so it should not be represented as an unqualified anticancer mechanism.</td>
</tr>
<tr>
<td>13</td>
<td>Glycolytic and lipid metabolism</td>
<td>↓ / dysregulated (model-dependent)</td>
<td>↔ / metabolically adaptive</td>
<td>R/G</td>
<td>Metabolic disruption</td>
<td>Metabolomic analysis in bladder cancer indicates altered anaerobic glycolysis and lipid synthesis downstream of ROS and AMPK. Evidence is presently tumor-model specific.</td>
</tr>
<tr>
<td>14</td>
<td>Clinical Translation Constraint</td>
<td>↓ effective systemic target exposure</td>
<td>Extensive first-pass metabolism</td>
<td>G</td>
<td>Exposure and evidence limitation</td>
<td>Many anticancer studies use 20–200 µM intact isoquercitrin. Human plasma after oral quercetin-3-glucoside contains predominantly glucuronidated and sulfated quercetin metabolites rather than intact isoquercitrin, making direct extrapolation from high-concentration cell studies uncertain. No established oncology efficacy in humans.</td>
</tr>
</tbody>
</table>
<p><b>TSF:</b> P: 0–30 min &nbsp;&nbsp;&nbsp; R: 30 min–3 hr &nbsp;&nbsp;&nbsp; G: &gt;3 hr</p>



<br><br>
<p><b>Alzheimer’s disease relevance:</b> Isoquercitrin has meaningful but entirely preclinical AD-related evidence. Reported effects include direct inhibition of β- and γ-secretase activity, ↓ Aβ aggregation with enhanced disaggregation in cell-free systems, ↓ amyloidogenic proteins including β-secretase and presenilins in animal models, ↓ neuronal oxidative stress, preservation of mitochondrial function, ↓ apoptosis, and improved learning and memory in Aβ- and streptozotocin-based rodent models. These findings support an anti-amyloidogenic and neuroprotective research classification, but there is currently no convincing human clinical evidence demonstrating prevention or treatment of Alzheimer’s disease.</p>

<p><b>Translation constraint:</b> Most AD evidence uses experimental Aβ25-35 injection, streptozotocin, cell-based amyloid systems, or other simplified models that do not reproduce the full biology of sporadic human AD. Oral metabolism also means that brain exposure to intact isoquercitrin is uncertain and circulating quercetin metabolites may contribute substantially to any systemic effect.</p>




<h3>Isoquercitrin Alzheimer-Relevant Mechanisms</h3>
<table border="1" cellpadding="4" cellspacing="0">
<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 β production and aggregation</td>
<td>↓ Aβ formation<br>↓ aggregation<br>↑ disaggregation</td>
<td>Reduced amyloid burden</td>
<td>Cell-free and cellular studies report direct anti-amyloidogenic activity; rodent studies show decreased brain amyloidosis-related proteins.</td>
</tr>
<tr>
<td>2</td>
<td>β-secretase</td>
<td>↓</td>
<td>Reduced amyloidogenic APP processing</td>
<td>Direct enzyme inhibition has been reported in vitro, and β-secretase expression is reduced in Aβ/HFD animal models.</td>
</tr>
<tr>
<td>3</td>
<td>γ-secretase and presenilins</td>
<td>↓ γ-secretase activity<br>↓ PS1<br>↓ PS2</td>
<td>Reduced Aβ-generating processing</td>
<td>Secretase inhibition is demonstrated in biochemical assays; reduced presenilin expression has been reported in mouse brain.</td>
</tr>
<tr>
<td>4</td>
<td>Neuronal oxidative stress</td>
<td>↓ ROS<br>↓ lipid peroxidation<br>↓ nitric oxide stress</td>
<td>Neuroprotection</td>
<td>Strong recurring mechanism across Aβ- and STZ-based experimental models.</td>
</tr>
<tr>
<td>5</td>
<td>Mitochondrial function</td>
<td>↑ preservation</td>
<td>Reduced neuronal energy failure</td>
<td>Isoquercitrin attenuates STZ-induced mitochondrial dysfunction and neuronal cytotoxicity.</td>
</tr>
<tr>
<td>6</td>
<td>Neuronal apoptosis</td>
<td>↓ caspase activation<br>↓ apoptosis</td>
<td>Improved neuronal survival</td>
<td>Opposite direction to many cancer models, illustrating disease- and stress-dependent modulation.</td>
</tr>
<tr>
<td>7</td>
<td>Proteasome function</td>
<td>↑ 20S chymotrypsin-like activity</td>
<td>Improved damaged-protein clearance</td>
<td>Reported in oxidative-stress APP cellular systems; translational importance remains uncertain.</td>
</tr>
<tr>
<td>8</td>
<td>Cognition and memory</td>
<td>↑</td>
<td>Improved behavioral performance</td>
<td>Improvement has been demonstrated in Aβ/HFD mouse and STZ rat models but not yet in human AD trials.</td>
</tr>
<tr>
<td>9</td>
<td>Clinical Translation Constraint</td>
<td>Preclinical only</td>
<td>Uncertain human efficacy</td>
<td>No established human AD efficacy; model validity, brain exposure, metabolism, and effective dose remain major uncertainties.</td>
</tr>
</tbody>
</table>