Description: <b>Fisetin</b> is a plant based flavonoid. Found in strawberries(160ug/g), apples, persimmons, onions, cucumbers, grapes.<br>
<br>
-Note <a href="tbResList.php?qv=78&tsv=1109&wNotes=on&exSp=open">half-life</a> 3-4hrs<br>
- Oral <a href="tbResList.php?qv=78&tsv=792&wNotes=on&exSp=open">BioAv</a> low (40-50%)
<br>
Pathways:<br>
<!-- ROS : MMP↓, ER Stress↑, Ca+2↑, Cyt‑c↑, Casp3↑, Casp9↑, DNAdam↑, UPR↑, cl-PARP↑-->
- induce
<a href="tbResList.php?qv=78&tsv=275&wNotes=on">ROS</a> production in cancer cells, but also known to reduce it. <br>
Also a claim
<a href="https://nestronics.ca/dbx/tbResEdit.php?rid=2855">Fisetin-Induced Reactive Oxygen Species Production Has No Effect on Apoptosis</a> in RCC cells
<br>
Also one claim (NAC 10-20mM levels) that
<a href="https://nestronics.ca/dbx/tbResEdit.php?rid=2856">NAC enhances ROS/apoptosis</a>
<br>
- ROS↑ related:
<a href="tbResList.php?qv=78&tsv=197&wNotes=on&word=MMP↓">MMP↓</a>(ΔΨm),
<a href="tbResList.php?qv=78&tsv=103&wNotes=on">ER Stress↑</a>,
<a href="tbResList.php?qv=78&tsv=459&wNotes=on">UPR↑</a>,
<a href="tbResList.php?qv=78&tsv=356&wNotes=on">GRP78↑</a>,
<a href="tbResList.php?qv=78&tsv=38&wNotes=on&word=Ca+2↑">Ca+2↑</a>,
<a href="tbResList.php?qv=78&tsv=77&wNotes=on">Cyt‑c↑</a>,
<a href="tbResList.php?qv=78&wNotes=on&word=Casp">Caspases↑</a>,
<a href="tbResList.php?qv=78&tsv=82&wNotes=on&word=DNAdam↑">DNA damage↑</a>,
<a href="tbResList.php?qv=78&tsv=239&wNotes=on">cl-PARP↑</a>,
<a href="tbResList.php?qv=78&wNotes=on&word=HSP">HSP↓</a>
<br>
<!-- ANTIOXIDANT : NRF2, SOD, GSH, CAT, HO-1, GPx, GPX4, -->
- Does not appear to lower antioxidants in cancer cells
<br>
- Raises
<a href="tbResList.php?qv=78&tsv=1103&wNotes=on&word=antiOx↑">AntiOxidant</a>
defense in Normal Cells:
<a href="tbResList.php?qv=78&tsv=275&wNotes=on&word=ROS↓">ROS↓</a>,
<a href="tbResList.php?qv=78&tsv=226&wNotes=on&word=NRF2↑">NRF2↑</a>,
<a href="tbResList.php?qv=78&tsv=298&wNotes=on&word=SOD↑">SOD↑</a>,
<a href="tbResList.php?qv=78&tsv=137&wNotes=on&word=GSH↑">GSH↑</a>,
<a href="tbResList.php?qv=78&tsv=46&wNotes=on&word=Catalase↑">Catalase↑</a>,
<br>
<!-- INFLAMMATION : NF-kB↓, COX2↓, COX2↓ PRO-INFL CYTOKINES: IL-1β↓, TNF-α↓, IL-6↓, IL-8↓, -->
- lowers
<a href="tbResList.php?qv=78&tsv=953&wNotes=on&word=Inflam">Inflammation</a> :
<a href="tbResList.php?qv=78&tsv=214&wNotes=on&word=NF-kB↓">NF-kB↓</a>,
<a href="tbResList.php?qv=78&tsv=66&wNotes=on&word=COX2↓">COX2↓</a>,
<a href="tbResList.php?qv=78&tsv=235&wNotes=on&word=p38↓">p38↓</a>, Pro-Inflammatory Cytokines :
<a href="tbResList.php?qv=78&tsv=978&wNotes=on&word=IL1β↓">IL-1β↓</a>,
<a href="tbResList.php?qv=78&tsv=309&wNotes=on&word=TNF-α↓">TNF-α↓</a>,
<a href="tbResList.php?qv=78&tsv=158&wNotes=on&word=IL6↓">IL-6↓</a>,
<br>
<!-- GROWTH/METASTASES : EMT↓, MMPs↓, MMP2↓, MMP9↓, IGF-1, uPA↓, VEGF↓, ERK↓
inhibiting metastasis-associated proteins such as ROCK1, FAK, (RhoA), NF-κB and u-PA, MMP-1 and MMP-13.-->
- inhibit Growth/Metastases :
<a href="tbResList.php?qv=78&tsv=604&wNotes=on">TumMeta↓</a>,
<a href="tbResList.php?qv=78&tsv=323&wNotes=on">TumCG↓</a>,
<a href="tbResList.php?qv=78&tsv=96&wNotes=on">EMT↓</a>,
<a href="tbResList.php?qv=78&tsv=204&wNotes=on">MMPs↓</a>,
<a href="tbResList.php?qv=78&tsv=201&wNotes=on">MMP2↓</a>,
<a href="tbResList.php?qv=78&tsv=203&wNotes=on">MMP9↓</a>,
<a href="tbResList.php?qv=78&tsv=415&wNotes=on">IGF-1↓</a>,
<a href="tbResList.php?qv=78&tsv=428&wNotes=on">uPA↓</a>,
<a href="tbResList.php?qv=78&tsv=334&wNotes=on">VEGF↓</a>,
<a href="tbResList.php?qv=78&tsv=110&wNotes=on">FAK↓</a>,
<a href="tbResList.php?qv=78&tsv=273&wNotes=on">RhoA↓</a>,
<a href="tbResList.php?qv=78&tsv=214&wNotes=on">NF-κB↓</a>,
<a href="tbResList.php?qv=78&tsv=304&wNotes=on">TGF-β↓</a>,
<a href="tbResList.php?qv=78&tsv=105&wNotes=on">ERK↓</a>
<br>
<!-- CELL CYCLE ARREST : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓ -->
- cause Cell cycle arrest :
<a href="tbResList.php?qv=78&tsv=322&wNotes=on">TumCCA↑</a>,
<a href="tbResList.php?qv=78&tsv=73&wNotes=on">cyclin D1↓</a>,
<a href="tbResList.php?qv=78&tsv=378&wNotes=on">cyclin E↓</a>,
<a href="tbResList.php?qv=78&tsv=467&wNotes=on">CDK2↓</a>,
<a href="tbResList.php?qv=78&tsv=894&wNotes=on">CDK4↓</a>,
<a href="tbResList.php?qv=78&tsv=895&wNotes=on">CDK6↓</a>,
<br>
<!-- MIGRATION/INVASION : TumCMig↓, TumCI↓, FAK↓, ERK↓, -->
- inhibits Migration/Invasion :
<a href="tbResList.php?qv=78&tsv=326&wNotes=on">TumCMig↓</a>,
<a href="tbResList.php?qv=78&tsv=324&wNotes=on">TumCI↓</a>,
<a href="tbResList.php?qv=78&tsv=110&wNotes=on">FAK↓</a>,
<a href="tbResList.php?qv=78&tsv=105&wNotes=on">ERK↓</a>,
<a href="tbResList.php?qv=78&tsv=96&wNotes=on">EMT↓</a>,
<a href="tbResList.php?qv=78&tsv=1117&wNotes=on">TOP1↓</a>,
<a href="tbResList.php?qv=78&tsv=657&wNotes=on">TET1↓</a>,
<br>
<!-- GLYCOLYSIS : ATP↓, HIF-1α↓, PKM2↓, cMyc↓, PDK1↓, GLUT1↓, LDHA↓, HK2↓, Glucose↓, GlucoseCon↓, lactateProd, OXPHOS -->
- inhibits
<a href="tbResList.php?qv=78&tsv=143&wNotes=on">HIF-1α↓</a>,
<a href="tbResList.php?qv=78&tsv=35&wNotes=on">cMyc↓</a>,
<a href="tbResList.php?qv=78&tsv=906&wNotes=on">LDH↓</a>,
<a href="tbResList.php?qv=78&tsv=356&wNotes=on">GRP78↑</a>,
<br>
<!-- ANGIOGENESIS : VEGF↓, VEGFR2↓, HIF-1α↓, NOTCH↓, FGF↓, PDGF↓, EGFR↓ ITG(Integrins↓)-->
- inhibits
<a href="tbResList.php?qv=78&tsv=447&wNotes=on">angiogenesis↓</a> :
<a href="tbResList.php?qv=78&tsv=334&wNotes=on">VEGF↓</a>,
<a href="tbResList.php?qv=78&tsv=143&wNotes=on">HIF-1α↓</a>,
<a href="tbResList.php?qv=78&tsv=94&wNotes=on&word=EGFR↓">EGFR↓</a>,
<br>
<!-- CSCs : CSC↓, CK2↓, Hh↓, GLi↓, GLi1↓, -->
- inhibits Cancer Stem Cells :
<a href="tbResList.php?qv=78&tsv=677&wNotes=on">CD133↓</a>,
<a href="tbResList.php?qv=78&tsv=342&wNotes=on">β-catenin↓</a>,
<br>
<!-- OTHERS : -->
- Others: <a href="tbResList.php?qv=78&tsv=252&wNotes=on">PI3K↓</a>,
<a href="tbResList.php?qv=78&tsv=4&wNotes=on">AKT↓</a>,
<a href="tbResList.php?qv=78&wNotes=on&word=JAK">JAK↓</a>,
<a href="tbResList.php?qv=78&wNotes=on&word=STAT">STAT↓</a>,
<a href="tbResList.php?qv=78&tsv=377&wNotes=on">Wnt↓</a>,
<a href="tbResList.php?qv=78&tsv=342&wNotes=on">β-catenin↓</a>,
<a href="tbResList.php?qv=78&tsv=9&wNotes=on">AMPK↓</a>,
<a href="tbResList.php?qv=78&tsv=105&wNotes=on">ERK↓</a>,
<a href="tbResList.php?qv=78&tsv=168&wNotes=on">JNK</a>,
<br>
<!-- SYNERGIES : -->
- Synergies:
<a href="tbResList.php?qv=78&tsv=1106&wNotes=on">chemo-sensitization</a>,
<a href="tbResList.php?qv=78&tsv=1171&wNotes=on">chemoProtective</a>,
<a href="tbResList.php?qv=78&tsv=1107&wNotes=on">RadioSensitizer</a>,
<a href="tbResList.php?qv=78&tsv=961&esv=2&wNotes=on&exSp=open">Others(review target notes)</a>,
<a href="tbResList.php?qv=78&tsv=1105&wNotes=on">Neuroprotective</a>,
<a href="tbResList.php?qv=78&tsv=557&wNotes=on">Cognitive</a>,
<a href="tbResList.php?qv=78&tsv=1175&wNotes=on">Renoprotection</a>,
<a href="tbResList.php?qv=78&tsv=1179&wNotes=on">Hepatoprotective</a>,
<a href="tbResList.php?&qv=78&tsv=1188&wNotes=on">CardioProtective</a>,
<br>
<br>
<!-- SELECTIVE: -->
- Selectivity:
<a href="tbResList.php?qv=78&tsv=1110&wNotes=on">Cancer Cells vs Normal Cells</a><br>
<br>
<p><b>Fisetin</b> — a naturally occurring plant flavonol and polyphenolic bioactive compound, chemically identified as 3,3′,4′,7-tetrahydroxyflavone. It is classified as a dietary flavonoid, experimental senotherapeutic and preclinical anticancer agent; Fisetin occurs in strawberries, apples, persimmons, grapes, onions and cucumbers, with strawberries providing one of the higher concentrations among commonly consumed foods. Its reported anticancer, neuroprotective and senolytic actions remain predominantly preclinical, and it is not an approved cancer or Alzheimer’s disease therapy.</p>
<p><b>Primary mechanisms (ranked):</b></p>
<ol>
<li>Suppression of PI3K/AKT/mTOR and related survival signaling, reducing tumor-cell proliferation, stress tolerance and treatment resistance.</li>
<li>Induction of intrinsic mitochondrial apoptosis through BAX/Bcl-2 rebalancing, mitochondrial membrane-potential loss, cytochrome-c release and caspase activation.</li>
<li>Inhibition of NF-κB, STAT3 and inflammatory survival transcription, with reductions in COX-2 and tumor-supportive cytokine signaling.</li>
<li>Cell-cycle arrest through reduced cyclin D1, cyclin E, CDK2, CDK4 and CDK6, accompanied in some models by increased p21 or p27.</li>
<li>Suppression of Wnt/β-catenin, EMT, matrix metalloproteinases and focal-adhesion signaling, reducing cancer stemness, migration and invasion.</li>
<li>Biphasic redox modulation: context-dependent ROS elevation and ER or mitochondrial stress in cancer cells, but antioxidant and NRF2-associated cytoprotection in many nonmalignant injury models.</li>
<li>Senotherapeutic activity against selected senescent-cell populations through disruption of senescent-cell anti-apoptotic pathways; selectivity varies markedly by cell type and dosing regimen.</li>
<li>Secondary inhibition of HIF-1α, VEGF and tumor-associated angiogenesis in responsive experimental models.</li>
</ol>
<p><b>Bioavailability / PK relevance:</b> Native fisetin has very low aqueous solubility, rapid intestinal and hepatic conjugation, and limited systemic exposure to unconjugated fisetin after conventional oral administration. Glucuronide, sulfate and methylated metabolites can predominate in circulation. Human PK evidence remains limited, although formulated preparations can produce substantially greater exposure than unformulated fisetin. Liposomal, nanoemulsion, phospholipid, cyclodextrin and other delivery systems are therefore mechanistically relevant but cannot be assumed equivalent to ordinary supplements.</p>
<p><b>In-vitro vs systemic exposure relevance:</b> Many anticancer experiments use approximately 10–100 µM fisetin, commonly 20–80 µM. These concentrations are substantially above the free-parent concentrations expected after ordinary dietary intake and may exceed those produced by conventional oral supplements. Direct translation of cytotoxic concentrations is therefore poor unless tumor accumulation, active metabolites or an exposure-enhancing formulation is demonstrated.</p>
<p><b>Clinical evidence status:</b> Cancer evidence is predominantly cell-culture and animal evidence. Early human studies are evaluating fisetin as a senolytic or supportive intervention in aging, frailty and cancer-survivor populations, but there is no completed randomized evidence establishing antitumor efficacy. Fisetin should be categorized as preclinical for direct cancer treatment and investigational for adjunct or senotherapeutic use.</p>
<p><b>Safety / interaction constraints:</b> Food-level exposure is generally regarded as low risk, and small short-term human studies have not identified a clear severe toxicity signal. However, high intermittent senolytic dosing and long-term supplemental dosing remain insufficiently characterized. Mechanistic concerns include antiplatelet or anticoagulant additivity, modulation of drug-metabolizing enzymes and transporters, topoisomerase inhibition, and context-dependent interference with oxidative or cytotoxic cancer treatments. Product purity and formulation-dependent exposure are additional uncertainties.</p>
<br>
<h3>Fisetin Mechanistic Ranking</h3>
<table border="1" cellspacing="0" cellpadding="4">
<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, ↓ AKT, ↓ mTORC1 and mTORC2</td>
<td>↔ or adaptive modulation</td>
<td>R–G</td>
<td>Reduced proliferation and survival</td>
<td>A recurrent mechanistic axis across prostate, breast, colorectal, lung and other experimental cancer models.</td>
</tr>
<tr>
<td>2</td>
<td>Mitochondrial intrinsic apoptosis</td>
<td>↑ BAX and BIM, ↓ Bcl-2 and Mcl-1, ↓ mitochondrial membrane potential, ↑ cytochrome-c and caspases</td>
<td>↔ generally preserved or protected (model-dependent)</td>
<td>R–G</td>
<td>Apoptotic tumor-cell death</td>
<td>Often downstream of survival-pathway inhibition, ER stress or redox disturbance rather than a single direct mitochondrial target.</td>
</tr>
<tr>
<td>3</td>
<td>NF-κB inflammatory survival signaling</td>
<td>↓ IKK and NF-κB activity, ↓ COX-2, ↓ anti-apoptotic transcription</td>
<td>↓ inflammatory NF-κB signaling</td>
<td>R–G</td>
<td>Reduced inflammation and stress resistance</td>
<td>Potentially relevant to both cancer-cell survival and the inflammatory tumor microenvironment.</td>
</tr>
<tr>
<td>4</td>
<td>Cell-cycle control</td>
<td>↑ G1 or G2/M arrest, ↓ cyclin D1 and cyclin E, ↓ CDK2, ↓ CDK4 and ↓ CDK6, ↑ p21 or p27</td>
<td>↔ or transient arrest (context-dependent)</td>
<td>G</td>
<td>Cytostatic growth suppression</td>
<td>The arrest point varies by cancer lineage, genotype, dose and treatment duration.</td>
</tr>
<tr>
<td>5</td>
<td>Wnt β-catenin and cancer stemness</td>
<td>↓ Wnt signaling, ↓ β-catenin, ↓ CD44 and CD133 (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Reduced stem-like phenotype and tumor propagation</td>
<td>Particularly relevant in colorectal and other tumors with active Wnt or β-catenin signaling.</td>
</tr>
<tr>
<td>6</td>
<td>EMT focal adhesion and matrix degradation</td>
<td>↓ EMT, ↓ FAK, ↓ RhoA and uPA, ↓ MMP-2 and MMP-9, ↑ E-cadherin</td>
<td>↔</td>
<td>G</td>
<td>Reduced migration, invasion and metastasis</td>
<td>Primarily preclinical phenotype data; suppression of several nodes is model-dependent.</td>
</tr>
<tr>
<td>7</td>
<td>ER stress and unfolded protein response</td>
<td>↑ PERK, ↑ eIF2α, ↑ ATF4 and CHOP, ↑ GRP78 or BiP (context-dependent)</td>
<td>↔ or ↓ pathological ER stress</td>
<td>R–G</td>
<td>Stress-mediated apoptosis</td>
<td>GRP78 induction may indicate stress activation rather than beneficial suppression; prolonged CHOP signaling favors death.</td>
</tr>
<tr>
<td>8</td>
<td>Mitochondrial ROS increase</td>
<td>↑ ROS and mtROS (dose-dependent), but ↓ or neutral ROS in some models</td>
<td>↓ ROS in oxidative-injury models</td>
<td>P–R</td>
<td>Biphasic redox modulation</td>
<td>ROS elevation is not universal or necessarily required for apoptosis. Direction depends on concentration, cell type and baseline oxidative state.</td>
</tr>
<tr>
<td>9</td>
<td>NRF2 antioxidant response</td>
<td>↑ or ↓ NRF2 (context-dependent)</td>
<td>↑ NRF2, ↑ HO-1, ↑ GSH, ↑ SOD and catalase</td>
<td>R–G</td>
<td>Adaptive antioxidant regulation</td>
<td>Predominantly protective in normal-tissue injury models; tumor-cell NRF2 activation could theoretically reduce treatment sensitivity.</td>
</tr>
<tr>
<td>10</td>
<td>Calcium ER mitochondrial stress</td>
<td>↑ cytosolic Ca²⁺ (model-dependent)</td>
<td>↔</td>
<td>P–R</td>
<td>Amplification of ER and mitochondrial apoptosis</td>
<td>Documented in selected models and should not be treated as a universal primary mechanism.</td>
</tr>
<tr>
<td>11</td>
<td>HIF-1α VEGF angiogenic signaling</td>
<td>↓ HIF-1α, ↓ VEGF and ↓ angiogenesis</td>
<td>↔ or vascular protection (injury-dependent)</td>
<td>G</td>
<td>Reduced hypoxic adaptation and neovascularization</td>
<td>Evidence is preclinical and is not equivalent to clinically validated antiangiogenic activity.</td>
</tr>
<tr>
<td>12</td>
<td>Glycolysis and metabolic adaptation</td>
<td>↓ HIF-1α, ↓ c-Myc and altered LDH or glycolytic activity (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Reduced metabolic flexibility</td>
<td>The database claim that fisetin uniformly inhibits glycolysis is too broad; direct evidence for comprehensive HK2, GLUT1, PKM2 and LDHA suppression is not consistent across models.</td>
</tr>
<tr>
<td>13</td>
<td>Senescent-cell survival networks</td>
<td>↓ survival of selected senescent tumor or stromal cells</td>
<td>↓ senescent-cell burden while sparing many nonsenescent cells (model-dependent)</td>
<td>G</td>
<td>Senolytic or senomorphic activity</td>
<td>Activity is heterogeneous and cannot be generalized to every senescent cell type. Effects on therapy-induced tumor senescence may be beneficial or contextually complex.</td>
</tr>
<tr>
<td>14</td>
<td>Chemosensitization and radiosensitization</td>
<td>↑ treatment response through ↓ AKT, ↓ NF-κB, apoptosis priming and possible DNA-damage enhancement</td>
<td>↔ or tissue protection (agent-dependent)</td>
<td>R–G</td>
<td>Potential adjunct sensitization</td>
<td>Preclinical only. Antioxidant effects in normal or tumor cells create treatment-specific uncertainty and require schedule-dependent evaluation.</td>
</tr>
<tr>
<td>15</td>
<td>Clinical Translation Constraint</td>
<td>Common effective in-vitro concentrations exceed ordinary systemic free-fisetin exposure</td>
<td>Human high-dose and long-term safety remain incompletely defined</td>
<td>G</td>
<td>Limited clinical translatability</td>
<td>Poor solubility, rapid conjugation, formulation dependence, tumor heterogeneity, uncertain active-metabolite contribution and absence of established anticancer efficacy are major constraints.</td>
</tr>
</tbody>
</table>
<p>P: 0–30 min R: 30 min–3 hr G: >3 hr</p>
<br><br>
<p><b>Alzheimer’s disease relevance:</b> Fisetin has significant but predominantly preclinical relevance to Alzheimer’s disease and related neurodegenerative disorders. Experimental studies report preservation of synaptic function and cognition, suppression of microglial inflammatory signaling, reduction of oxidative stress, promotion of autophagic clearance of phosphorylated tau, and modulation of amyloid-associated toxicity. Senescent-cell clearance provides an additional emerging rationale, but the relative contribution of senolysis versus direct neuroprotective signaling is unresolved. A pilot clinical study in mild cognitive impairment or mild Alzheimer’s disease is registered, but no completed trial currently establishes cognitive efficacy.</p>
<p><b>Exposure constraint:</b> Most neurological evidence comes from cell and animal models. Native fisetin’s poor solubility, rapid conjugation and uncertain free-brain exposure materially limit direct translation. CMS121 and other fisetin-derived compounds are being developed partly to improve potency, metabolic stability and neuroprotective exposure.</p>
<h3>Fisetin in Alzheimer’s Disease</h3>
<table border="1" cellspacing="0" cellpadding="4">
<thead>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Modulation</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
</thead>
<tbody>
<tr>
<td>1</td>
<td>Neuroinflammation and microglial activation</td>
<td>↓ NF-κB, ↓ inflammatory microglial activation, ↓ pro-inflammatory mediators</td>
<td>R–G</td>
<td>Reduced chronic neuroinflammatory stress</td>
<td>One of the more consistent neuroprotective mechanisms in cellular and animal models.</td>
</tr>
<tr>
<td>2</td>
<td>Synaptic plasticity and ERK CREB signaling</td>
<td>↑ ERK-dependent synaptic signaling and long-term potentiation (context-dependent)</td>
<td>R–G</td>
<td>Preservation of learning and memory</td>
<td>Neuronal ERK activation differs from the ERK suppression reported in many cancer models.</td>
</tr>
<tr>
<td>3</td>
<td>Tau autophagic clearance</td>
<td>↑ TFEB and autophagic processing, ↓ phosphorylated tau accumulation</td>
<td>G</td>
<td>Improved proteostasis</td>
<td>Demonstrated preclinically; human relevance and required brain exposure remain unknown.</td>
</tr>
<tr>
<td>4</td>
<td>Amyloid β toxicity and aggregation</td>
<td>↓ amyloid-associated oxidative injury and fibril formation (model-dependent)</td>
<td>G</td>
<td>Reduced amyloid-mediated neuronal stress</td>
<td>Evidence does not establish clinically meaningful plaque removal.</td>
</tr>
<tr>
<td>5</td>
<td>NRF2 antioxidant defense</td>
<td>↑ NRF2, ↑ HO-1 and endogenous antioxidant capacity</td>
<td>R–G</td>
<td>Protection from oxidative neuronal injury</td>
<td>Protective signaling may cooperate with TFEB-mediated proteostasis.</td>
</tr>
<tr>
<td>6</td>
<td>Neuronal mitochondria and apoptosis</td>
<td>↓ mitochondrial dysfunction, ↓ ROS and ↓ apoptotic signaling</td>
<td>R–G</td>
<td>Improved neuronal survival</td>
<td>Direction is opposite to the pro-oxidant mitochondrial stress sought in many cancer models.</td>
</tr>
<tr>
<td>7</td>
<td>Cellular senescence and SASP</td>
<td>↓ selected senescent-cell burden and ↓ senescence-associated inflammatory signaling</td>
<td>G</td>
<td>Potential reduction of age-related neuroinflammation</td>
<td>Mechanistically plausible but not yet clinically validated in Alzheimer’s disease.</td>
</tr>
<tr>
<td>8</td>
<td>Clinical Translation Constraint</td>
<td>Limited and formulation-dependent systemic and brain exposure; no established therapeutic dose</td>
<td>G</td>
<td>Uncertain human efficacy</td>
<td>Registered pilot testing does not yet constitute efficacy evidence. Native fisetin may not reproduce the exposure or pharmacology of optimized derivatives.</td>
</tr>
</tbody>
</table>
<p>P: 0–30 min R: 30 min–3 hr G: >3 hr</p>