Description: <p><b>Artemisinin</b> — a plant-derived sesquiterpene lactone endoperoxide (from <i>Artemisia annua</i>) best known as the parent scaffold for artemisinin-class antimalarials and widely investigated as a tumor-selective redox/iron-reactive cytotoxic agent. It is a small-molecule natural product (drug-like phytochemical) whose major clinical derivatives include artesunate (water-soluble), artemether/arteether (lipophilic), and the active metabolite dihydroartemisinin (DHA). In oncology literature the abbreviation set commonly includes ART (artemisinin), AS (artesunate), and DHA (dihydroartemisinin); many mechanistic claims are derivative-specific and exposure/iron-context dependent.</p>
<p><b>Primary mechanisms (ranked):</b></p>
<ol>
<li>Iron-dependent activation of the endoperoxide bridge causing ROS/lipid peroxidation stress and tumor-selective cytotoxicity (iron-high contexts)</li>
<li>Ferroptosis sensitization/induction via iron handling and lipid peroxidation programs (often linked to ferritin/lysosome biology; context-dependent)</li>
<li>Mitochondrial dysfunction with ΔΨm loss and intrinsic apoptosis signaling (downstream of oxidative stress)</li>
<li>ER stress / UPR activation (stress-amplification axis)</li>
<li>Hypoxia–metabolism suppression (HIF-1α and glycolysis program attenuation; model-dependent)</li>
<li>Pro-survival inflammatory signaling suppression (e.g., NF-κB / STAT3 axes; model-dependent)</li>
</ol>
<p><b>Bioavailability / PK relevance:</b> Oral artemisinin has variable and generally limited systemic exposure with a short half-life on the order of hours; many anticancer in-vitro concentrations exceed typical achievable free-plasma levels without formulation strategies. Artesunate is rapidly converted to DHA; in an FDA label dataset (IV artesunate for severe malaria), artesunate has a very short half-life (~0.3 h) and DHA ~1.3 h, emphasizing exposure-time constraints and the need to interpret “ART/AS/DHA” PK separately.</p>
<p><b>In-vitro vs systemic exposure relevance:</b> Many reported anticancer effects are driven by oxidative stress at micromolar in-vitro conditions and may be difficult to reproduce systemically without targeted delivery, local administration, or combination strategies that increase intratumoral iron/ROS burden (context-dependent).</p>
<p><b>Clinical evidence status:</b> Cancer use remains investigational (preclinical-dominant with small/early human studies). Multiple registered clinical studies have evaluated artesunate/derivatives in oncology settings (e.g., phase I solid tumor IV artesunate; small/phase II-style neoadjuvant/adjunct trials), but there is no major regulatory approval for cancer indications; artesunate is approved/used clinically for severe malaria.</p>
<b>Artemisinin</b> a compound in a Chinese herb that may inhibit tumor growth and metastasis
Artemisinin (antimalarial drugs)<br>
Artesunic acid (Artesunate) , Dihydroartemisinin (DHA), artesunate, arteether, and artemether, SM735, SM905, SM933, SM934, and SM1044 <br>
<br>
The induction of OS in tumor cells via the production of ROS is the key mechanism of ART against cancer.<br>
combination of ART and Nrf2 inhibitors to promote ferroptosis may have more efficient anticancer effects without damaging normal cells.<br>
<br>
Summary:<br>
- One of the strongest tumor-selective pro-oxidants, mechanism related with iron. Synergizes with iron-rich tumors<br>
-<a href="tbResList.php?qv=34&tsv=275&wNotes=on">ROS</a> seems to affect both cancer and normal cells<br>
- Delivery of <a href="tbResEdit.php?rid=2577">
artemisinin in conjugate form with transferrin</a> or holotransferrin (serum iron transport proteins) have been shown to greatly improve its effectiveness.<br>
- Potential direct inhibitor of
<a href="tbResList.php?qv=34&tsv=373&wNotes=on&exSp=open">STAT3 </a><br>
- <a href="tbResList.php?qv=34&qv2=19&wNotes=on&exSp=open">
Artemisinin synergized with the glycolysis inhibitor 2DG</a> (2-deoxy- D -glucose)<br>
ART Combined Therapy:
<a href="tbResList.php?qv=34&qv2=27&wNotes=on&exSp=open">Allicin</a>,
<a href="tbResList.php?qv=34&qv2=141&wNotes=on&exSp=open">Resveratrol</a>,
<a href="tbResList.php?qv=34&qv2=65&wNotes=on&exSp=open">Curcumin</a>,
<a href="tbResList.php?qv=34&qv2=166&wNotes=on&exSp=open">VitC</a> (but not orally at same time),
<a href="tbResList.php?qv=34&qv2=15&wNotes=on&exSp=open">Butyrate </a>,
<a href="tbResList.php?qv=34&qv2=19&wNotes=on&exSp=open">2-DG</a>,
<a href="tbResList.php?qv=34&qv2=332&wNotes=on&exSp=open">Aminolevulinic AcidG</a>
<br>
-possible problems with <a href="tbResEdit.php?rid=2571">liver toxicity??</a><br>
<br>
-Artesunate (ART), an artemisinin compound, is known for lysosomal degradation of ferritin, inducing oxidative stress and promoting cancer cell death.<br>
<br>
Pathways:<br>
- Increasing reactive oxygen species (ROS) production. This oxidative stress can cause the loss of mitochondrial membrane potential, leading to cytochrome c release and subsequent activation of caspase cascades.<br>
- Downregulate HIF-1α<br>
- By impairing glycolysis, artemisinin might force cells to rely on oxidative phosphorylation (OXPHOS) for energy production.<br>
- Inhibit GLUT1 (glucose uptake), HK2, PKM2 (slow the glycolytic flux, thereby reducing the energy supply)<br>
- Minimal NRF2 activation<br>
<br>
-Artemisinin has a <a href="tbResList.php?qv=34&&tsv=1109&wNotes=on&exSp=open">half-life </a> of about 3-4 hours, Artesunate 40 minutes and Artemether 12 hours. Peak plasma levels occur in 1-2 hour.<br>
<a href="tbResList.php?qv=34&tsv=792&wNotes=on&exSp=open">BioAv</a> 21%, poor-good solubility. Artesunate (ART), a water soluble derivative of artemisinin. concentrations higher in blood, colon, liver, kidney (highly perfused organs)
<br>
Pathways:<br>
<!-- ROS : MMP↓, ER Stress↑, Ca+2↑, Cyt‑c↑, Casp3↑, Casp9↑, DNAdam↑, UPR↑, cl-PARP↑-->
- induce
<a href="tbResList.php?qv=34&tsv=275&wNotes=on">ROS</a> production, iron dependent (affect both cancer and normal cells)<br>
- ROS↑ related:
<a href="tbResList.php?qv=34&tsv=197&wNotes=on&word=MMP↓">MMP↓</a>(ΔΨm),
<a href="tbResList.php?qv=34&tsv=103&wNotes=on">ER Stress↑</a>,
<a href="tbResList.php?qv=34&tsv=459&wNotes=on">UPR↑</a>,
<a href="tbResList.php?qv=34&tsv=356&wNotes=on">GRP78↑</a>,
<a href="tbResList.php?qv=34&tsv=38&wNotes=on&word=Ca+2↑">Ca+2↑</a>,
<a href="tbResList.php?qv=34&tsv=77&wNotes=on">Cyt‑c↑</a>,
<a href="tbResList.php?qv=34&wNotes=on&word=Casp">Caspases↑</a>,
<a href="tbResList.php?qv=34&tsv=82&wNotes=on&word=DNAdam↑">DNA damage↑</a>,
<a href="tbResList.php?qv=34&tsv=239&wNotes=on">cl-PARP↑</a>,
<a href="tbResList.php?qv=34&wNotes=on&word=HSP">HSP↓</a>,
<!-- <a href="tbResList.php?qv=34&wNotes=on&word=Prx">Prx</a>,--><!-- mitochondrial antioxidant enzyme-->
<br>
<!-- ANTIOXIDANT : NRF2, SOD, GSH, CAT, HO-1, GPx, GPX4, -->
- Both Lowers (and raises) AntiOxidant defense in Cancer Cells:
<a href="tbResList.php?qv=34&tsv=226&wNotes=on&word=NRF2">NRF2↓</a>(contary),
<!-- <a href="tbResList.php?qv=34&word=Trx&wNotes=on">TrxR↓**</a>, --><!-- major antioxidant system -->
<a href="tbResList.php?qv=34&tsv=298&wNotes=on&word=SOD↓">SOD↓</a>,
<a href="tbResList.php?qv=34&tsv=137&wNotes=on&word=GSH↓">GSH↓</a>
<a href="tbResList.php?qv=34&tsv=46&wNotes=on">Catalase↓</a>
<!-- <a href="tbResList.php?qv=34&tsv=597&wNotes=on">HO1↓</a> -->
<a href="tbResList.php?qv=34&wNotes=on&word=GPx">GPx↓</a>
<br>
- Small evidence of Raising
<a href="tbResList.php?qv=34&tsv=1103&wNotes=on&word=antiOx↑">AntiOxidant</a>
defense in Normal Cells:
<a href="tbResList.php?qv=34&tsv=275&wNotes=on&word=ROS">ROS↓</a>(contary),
<a href="tbResList.php?qv=34&tsv=226&wNotes=on&word=NRF2↑">NRF2↑</a>,
<a href="tbResList.php?qv=34&tsv=298&wNotes=on&word=SOD↑">SOD↑</a>(contary),
<a href="tbResList.php?qv=34&tsv=137&wNotes=on&word=GSH↑">GSH↑</a>,
<a href="tbResList.php?qv=34&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=34&tsv=953&wNotes=on&word=Inflam">Inflammation</a> :
<a href="tbResList.php?qv=34&tsv=214&wNotes=on&word=NF-kB↓">NF-kB↓</a>,
<a href="tbResList.php?qv=34&tsv=66&wNotes=on&word=COX2↓">COX2↓</a>,
<a href="tbResList.php?qv=34&tsv=235&wNotes=on&word=p38↓">p38↓</a>, Pro-Inflammatory Cytokines :
<a href="tbResList.php?qv=34&tsv=908&wNotes=on&word=NLRP3↓">NLRP3↓</a>,
<!-- <a href="tbResList.php?qv=34&tsv=978&wNotes=on&word=IL1β↓">IL-1β↓</a>, -->
<a href="tbResList.php?qv=34&tsv=309&wNotes=on&word=TNF-α↓">TNF-α↓</a>,
<a href="tbResList.php?qv=34&tsv=158&wNotes=on&word=IL6↓">IL-6↓</a>,
<a href="tbResList.php?qv=34&tsv=368&wNotes=on&word=IL8↓">IL-8↓</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=34&tsv=604&wNotes=on">TumMeta↓</a>,
<a href="tbResList.php?qv=34&tsv=323&wNotes=on">TumCG↓</a>,
<a href="tbResList.php?qv=34&tsv=96&wNotes=on">EMT↓</a>,
<a href="tbResList.php?qv=34&tsv=204&wNotes=on">MMPs↓</a>,
<a href="tbResList.php?qv=34&tsv=201&wNotes=on">MMP2↓</a>,
<a href="tbResList.php?qv=34&tsv=203&wNotes=on">MMP9↓</a>,
<a href="tbResList.php?qv=34&tsv=308&wNotes=on">TIMP2</a>,
<a href="tbResList.php?qv=34&wNotes=on&word=IGF">IGF-1↓</a>,
<a href="tbResList.php?qv=34&tsv=428&wNotes=on">uPA↓</a>,
<a href="tbResList.php?qv=34&tsv=334&wNotes=on">VEGF↓</a>,
<a href="tbResList.php?qv=34&tsv=1284&wNotes=on">ROCK1↓</a>,
<!-- <a href="tbResList.php?qv=34&tsv=110&wNotes=on">FAK↓</a>, -->
<!-- <a href="tbResList.php?qv=34&tsv=273&wNotes=on">RhoA↓</a>, -->
<a href="tbResList.php?qv=34&tsv=214&wNotes=on">NF-κB↓</a>,
<!-- <a href="tbResList.php?qv=34&tsv=79&wNotes=on">CXCR4↓</a>, -->
<!-- <a href="tbResList.php?qv=34&tsv=1247&wNotes=on">SDF1↓</a>, -->
<a href="tbResList.php?qv=34&tsv=304&wNotes=on">TGF-β↓</a>,
<!-- <a href="tbResList.php?qv=34&tsv=719&wNotes=on">α-SMA↓</a>, -->
<a href="tbResList.php?qv=34&tsv=105&wNotes=on">ERK↓</a>
<!-- <a href="tbResList.php?qv=34&tsv=1178&wNotes=on">MARK4↓</a> --><!-- contributing to tumor growth, invasion, and metastasis-->
<br>
<!-- REACTIVATE GENES : HDAC↓, DNMT1↓, DNMT3A↓, EZH2↓, P53↑, -->
<!--
- reactivate genes thereby inhibiting cancer cell growth :
<a href="tbResList.php?qv=34&tsv=140&wNotes=on">HDAC↓</a>,
<a href="tbResList.php?qv=34&wNotes=on&word=DNMT">DNMTs↓</a>,
<a href="tbResList.php?qv=34&tsv=108&wNotes=on">EZH2↓</a>,
<a href="tbResList.php?qv=34&tsv=236&wNotes=on">P53↑</a>,
<a href="tbResList.php?qv=34&wNotes=on&word=HSP">HSP↓</a>,
<a href="tbResList.php?qv=34&tsv=506&wNotes=on">Sp proteins↓</a>,
<a href="tbResList.php?qv=34&wNotes=on&word=TET">TET↑</a>
<br> -->
<!-- CELL CYCLE ARREST : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓ -->
- cause Cell cycle arrest :
<a href="tbResList.php?qv=34&tsv=322&wNotes=on">TumCCA↑</a>,
<a href="tbResList.php?qv=34&tsv=73&wNotes=on">cyclin D1↓</a>,
<a href="tbResList.php?qv=34&tsv=378&wNotes=on">cyclin E↓</a>,
<a href="tbResList.php?qv=34&tsv=467&wNotes=on">CDK2↓</a>,
<a href="tbResList.php?qv=34&tsv=894&wNotes=on">CDK4↓</a>,
<a href="tbResList.php?qv=34&tsv=895&wNotes=on">CDK6↓</a>,
<br>
<!-- MIGRATION/INVASION : TumCMig↓, TumCI↓, FAK↓, ERK↓, -->
- inhibits Migration/Invasion :
<a href="tbResList.php?qv=34&tsv=326&wNotes=on">TumCMig↓</a>,
<a href="tbResList.php?qv=34&tsv=324&wNotes=on">TumCI↓</a>,
<a href="tbResList.php?qv=34&tsv=309&wNotes=on&word=TNF-α↓">TNF-α↓</a>, <!-- encourages invasion, proliferation, EMT, and angiogenesis -->
<!-- <a href="tbResList.php?qv=34&tsv=110&wNotes=on">FAK↓</a>, -->
<a href="tbResList.php?qv=34&tsv=105&wNotes=on">ERK↓</a>,
<a href="tbResList.php?qv=34&tsv=96&wNotes=on">EMT↓</a>,
<a href="tbResList.php?qv=34&wNotes=on&word=TOP">TOP1↓</a>,
<!-- <a href="tbResList.php?qv=34&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=34&tsv=129&wNotes=on">glycolysis</a>
/<a href="tbResList.php?qv=34&tsv=947&wNotes=on">Warburg Effect</a> and
<a href="tbResList.php?qv=34&tsv=21&wNotes=on&word=ATP↓">ATP depletion</a> :
<a href="tbResList.php?qv=34&tsv=143&wNotes=on">HIF-1α↓</a>,
<a href="tbResList.php?qv=34&tsv=772&wNotes=on">PKM2↓</a>,
<a href="tbResList.php?qv=34&tsv=35&wNotes=on">cMyc↓</a>,
<a href="tbResList.php?qv=34&tsv=566&wNotes=on&word=GLUT">GLUT1↓</a>,
<a href="tbResList.php?qv=34&tsv=906&wNotes=on">LDH↓</a>,
<a href="tbResList.php?qv=34&tsv=175&wNotes=on&word=LDH">LDHA↓</a>,
<a href="tbResList.php?qv=34&tsv=773&wNotes=on">HK2↓</a>,
<!-- <a href="tbResList.php?qv=34&wNotes=on&word=PFK">PFKs↓</a>, -->
<!-- <a href="tbResList.php?qv=34&wNotes=on&word=PDK">PDKs↓</a>, -->
<a href="tbResList.php?qv=34&tsv=847&wNotes=on">ECAR↓</a>,
<!-- <a href="tbResList.php?qv=34&tsv=230&wNotes=on">OXPHOS↓</a>, -->
<a href="tbResList.php?qv=34&tsv=356&wNotes=on">GRP78↑</a>,
<!-- <a href="tbResList.php?qv=34&tsv=1278&wNotes=on">Glucose↓</a>, -->
<a href="tbResList.php?qv=34&tsv=623&wNotes=on">GlucoseCon↓</a>
<br>
<!-- ANGIOGENESIS : VEGF↓, VEGFR2↓, HIF-1α↓, NOTCH↓, FGF↓, PDGF↓, EGFR↓ ITG(Integrins↓)-->
- inhibits
<a href="tbResList.php?qv=34&tsv=447&wNotes=on">angiogenesis↓</a> :
<a href="tbResList.php?qv=34&tsv=334&wNotes=on">VEGF↓</a>,
<a href="tbResList.php?qv=34&tsv=143&wNotes=on">HIF-1α↓</a>,
<!-- <a href="tbResList.php?qv=34&wNotes=on&word=NOTCH">Notch↓</a>, -->
<!-- <a href="tbResList.php?qv=34&wNotes=on&word=FGF">FGF↓</a>, -->
<!-- <a href="tbResList.php?qv=34&wNotes=on&word=PDGF">PDGF↓</a>, -->
<a href="tbResList.php?qv=34&tsv=94&wNotes=on&word=EGFR↓">EGFR↓</a>,
<a href="tbResList.php?qv=34&&wNotes=on&word=ITG">Integrins↓</a>,
<br>
<!-- CSCs : CSC↓, CK2↓, Hh↓, GLi↓, GLi1↓, -->
- some small indication of inhibiting Cancer Stem Cells :
<a href="tbResList.php?qv=34&tsv=795&wNotes=on">CSC↓</a>,
<!-- <a href="tbResList.php?qv=34&tsv=524&wNotes=on">CK2↓</a>, -->
<a href="tbResList.php?qv=34&tsv=141&wNotes=on">Hh↓</a>,
<!-- <a href="tbResList.php?qv=34&tsv=434&wNotes=on">GLi↓</a>, -->
<!-- <a href="tbResList.php?qv=34&tsv=124&wNotes=on">GLi1↓</a>, -->
<!-- <a href="tbResList.php?qv=34&tsv=677&wNotes=on">CD133↓</a>, -->
<!-- <a href="tbResList.php?qv=34&tsv=655&wNotes=on">CD24↓</a>, -->
<a href="tbResList.php?qv=34&tsv=342&wNotes=on">β-catenin↓</a>,
<!-- <a href="tbResList.php?qv=34&tsv=357&wNotes=on">n-myc↓</a>, -->
<a href="tbResList.php?qv=34&tsv=656&wNotes=on">sox2↓</a>,
<!-- <a href="tbResList.php?qv=34&wNotes=on&word=NOTCH">Notch2↓</a>, -->
<!-- <a href="tbResList.php?qv=34&tsv=1024&wNotes=on">nestin↓</a>, -->
<a href="tbResList.php?qv=34&tsv=508&wNotes=on">OCT4↓</a>,
<br>
<!-- OTHERS : -->
- Others: <a href="tbResList.php?qv=34&tsv=252&wNotes=on">PI3K↓</a>,
<a href="tbResList.php?qv=34&tsv=4&wNotes=on">AKT↓</a>,
<a href="tbResList.php?qv=34&wNotes=on&word=JAK">JAK↓</a>,
<a href="tbResList.php?qv=34&wNotes=on&word=STAT">STAT↓</a>,
<a href="tbResList.php?qv=34&tsv=377&wNotes=on">Wnt↓</a>,
<a href="tbResList.php?qv=34&tsv=342&wNotes=on">β-catenin↓</a>,
<a href="tbResList.php?qv=34&tsv=9&wNotes=on">AMPK</a>,
<!-- <a href="tbResList.php?qv=34&tsv=475&wNotes=on">α↓</a>, -->
<a href="tbResList.php?qv=34&tsv=105&wNotes=on">ERK↓</a>,
<!-- <a href="tbResList.php?qv=34&tsv=1014&wNotes=on">5↓</a>, -->
<a href="tbResList.php?qv=34&tsv=168&wNotes=on">JNK</a>,
<!-- - <a href="tbResList.php?qv=34&wNotes=on&word=SREBP">SREBP</a> (related to cholesterol). -->
<br>
<!-- SYNERGIES : -->
- Synergies:
<a href="tbResList.php?qv=34&tsv=1106&wNotes=on">chemo-sensitization</a>,
<!-- <a href="tbResList.php?qv=34&tsv=1171&wNotes=on">chemoProtective</a>, -->
<a href="tbResList.php?qv=34&tsv=1107&wNotes=on">RadioSensitizer</a>,
<!-- <a href="tbResList.php?qv=34&tsv=1185&wNotes=on">RadioProtective</a>, -->
<a href="tbResList.php?qv=34&tsv=961&esv=2&wNotes=on&exSp=open">Others(review target notes)</a>,
<!-- <a href="tbResList.php?qv=34&tsv=1105&wNotes=on">Neuroprotective</a>, -->
<!-- <a href="tbResList.php?qv=34&tsv=557&wNotes=on">Cognitive</a>, -->
<!-- <a href="tbResList.php?qv=34&tsv=1175&wNotes=on">Renoprotection</a>, -->
<!-- <a href="tbResList.php?qv=34&tsv=1179&wNotes=on">Hepatoprotective</a>, -->
<!-- <a href="tbResList.php?&qv=34&tsv=1188&wNotes=on">CardioProtective</a>, -->
<br>
<br>
<!-- SELECTIVE: -->
- Selectivity:
<a href="tbResList.php?qv=34&tsv=1110&wNotes=on">Cancer Cells vs Normal Cells</a>
<br>
Often synergistic with ROS-based chemo<br>
<br>
<h3>Artemisinin-class (ART/AS/DHA) mechanisms relevant to cancer biology</h3>
<table>
<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>Iron-activated endoperoxide chemistry and ROS burden</td>
<td>ROS↑, lipid peroxidation↑, macromolecular damage↑ (iron-high contexts)</td>
<td>ROS↔ to ↑ (dose-dependent)</td>
<td>P</td>
<td>Pro-oxidant, tumor-biased cytotoxic stress</td>
<td>Core premise: iron availability (labile iron pool, heme/Fe²⁺ context) gates potency and selectivity; derivative and formulation matter.</td>
</tr>
<tr>
<td>2</td>
<td>Ferroptosis susceptibility</td>
<td>Ferroptosis↑ (context-dependent), lipid-ROS↑</td>
<td>Ferroptosis↔ (context-dependent)</td>
<td>R</td>
<td>Non-apoptotic death program engagement or sensitization</td>
<td>Evidence supports artemisinin-compounds as ferroptosis sensitizers/inducers in multiple models; often tied to iron handling and lipid peroxidation control nodes.</td>
</tr>
<tr>
<td>3</td>
<td>Ferritin and lysosome axis</td>
<td>Ferritin turnover↑ / lysosomal iron↑ (model-dependent) → ROS↑</td>
<td>↔ (model-dependent)</td>
<td>R</td>
<td>Iron mobilization that amplifies oxidative injury</td>
<td>DHA/derivatives have been reported to engage ferritin/lysosome-related processes that increase reactive iron, supporting ferroptotic and apoptotic stress amplification.</td>
</tr>
<tr>
<td>4</td>
<td>Mitochondria and MPTP</td>
<td>ΔΨm↓, mitochondrial ROS↑, Cyt-c release↑, apoptosis↑</td>
<td>Stress responses↔ to ↑ (dose-dependent)</td>
<td>R</td>
<td>Intrinsic apoptosis downstream of redox injury</td>
<td>Mitochondrial impairment is commonly reported as a downstream execution route after ROS/iron activation; can intersect with ferroptosis via redox spillover.</td>
</tr>
<tr>
<td>5</td>
<td>ER stress and UPR</td>
<td>ER stress↑, UPR↑</td>
<td>↔ to ↑ (stress-dose dependent)</td>
<td>R</td>
<td>Proteostasis collapse / stress signaling</td>
<td>Often co-occurs with ROS-driven injury; may contribute to growth arrest and death pathway crosstalk.</td>
</tr>
<tr>
<td>6</td>
<td>HIF-1α axis</td>
<td>HIF-1α↓ (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Anti-hypoxic adaptation</td>
<td>Reported suppression of hypoxia programs may reduce angiogenic and glycolytic adaptation in some tumors.</td>
</tr>
<tr>
<td>7</td>
<td>Glycolysis and glucose transport</td>
<td>Glycolysis↓, GLUT1/HK2/PKM2↓ (model-dependent)</td>
<td>↔ (context-dependent)</td>
<td>G</td>
<td>Metabolic constraint</td>
<td>Metabolic effects vary by cell state; can synergize with glycolysis inhibitors in model systems.</td>
</tr>
<tr>
<td>8</td>
<td>STAT3 axis</td>
<td>STAT3↓ (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Pro-survival transcriptional attenuation</td>
<td>Reported in subsets of studies; may contribute to reduced proliferation/survival signaling.</td>
</tr>
<tr>
<td>9</td>
<td>NF-κB and inflammatory signaling</td>
<td>NF-κB↓, inflammatory cytokine programs↓ (model-dependent)</td>
<td>Inflammation↓ (context-dependent)</td>
<td>G</td>
<td>Anti-inflammatory / pro-differentiation pressure</td>
<td>Can be beneficial for tumor microenvironment modulation, but directionality and net effect depend on immune context.</td>
</tr>
<tr>
<td>10</td>
<td>NRF2 axis</td>
<td>NRF2↔ (model-dependent; adaptive resistance possible)</td>
<td>NRF2↔ to ↑ (context-dependent)</td>
<td>G</td>
<td>Redox adaptation gatekeeper</td>
<td>NRF2 status can determine sensitivity vs resistance to ROS/ferroptosis; combinations that blunt NRF2 defenses are often proposed experimentally.</td>
</tr>
<tr>
<td>11</td>
<td>Clinical Translation Constraint</td>
<td>Short exposure window; achievable concentrations may be below many in-vitro active ranges; heterogeneity in iron/redox state; derivative-specific PK</td>
<td>Off-target oxidative stress risk (dose/formulation dependent)</td>
<td>G</td>
<td>Limits systemic reproducibility</td>
<td>Interpret ART vs AS vs DHA separately; artesunate→DHA conversion is rapid and half-lives are short (route-dependent). Targeted delivery and combination strategies are common translational approaches.</td>
</tr>
</table>
<p><b>TSF legend:</b> P: 0–30 min R: 30 min–3 hr G: >3 hr</p>