Description: <p><b>γ-Linolenic acid (GLA)</b> — an omega-6 polyunsaturated fatty acid (18:3 n-6) found in high concentration in <b>borage oil</b>, evening primrose oil, and blackcurrant seed oil. Metabolized to dihomo-γ-linolenic acid (DGLA) → precursor of anti-inflammatory eicosanoids (e.g., PGE1).</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) Membrane lipid remodeling → altered eicosanoid balance (↑ PGE1; DGLA-derived metabolites)<br>
2) Modulation of inflammatory signaling (↓ NF-κB tone; context-dependent)<br>
3) Lipid peroxidation susceptibility (PUFA-driven ROS shifts)<br>
4) Potential anti-proliferative effects (high concentration only; tumor models)<br>
5) Metabolic signaling interaction (PPAR activation context-dependent)</p>
<p><b>Bioavailability / PK relevance:</b> Orally absorbed and incorporated into membrane phospholipids; rapidly elongated to DGLA. Plasma levels achievable with supplementation; cellular effects reflect incorporation over days–weeks (remodeling).</p>
<p><b>In-vitro vs oral exposure:</b> Direct tumor cytotoxicity generally observed at supra-physiologic concentrations; physiologic doses mainly alter lipid signaling rather than induce apoptosis.</p>
<p><b>Clinical evidence status:</b> Used for inflammatory conditions (e.g., dermatitis, RA); oncology data limited and inconsistent; no cancer approval.</p>
<b>GLA</b> (abundant in borage oil) has shown anti-proliferative and pro-apoptotic effects on multiple cancer cell lines and in animal models (mechanisms include ER stress, mitochondrial dysfunction, altered eicosanoid signaling).<br>
-Borage plants can contain unsaturated PAs(Pyrrolizidine alkaloids) which are hepatotoxic and genotoxic/carcinogenic. Many authorities advise only using borage oil products certified PA-free, and caution against long-term or high-dose use.</br>
-γ-gamma linolenic acid (GLA, 18:3n-6) are polyunsaturated fatty acids (PUFA) that improve the human health<br>
<br>
<h3>γ-Linolenic Acid (Borage Oil) — 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>Membrane lipid remodeling (DGLA incorporation)</td>
<td>↑ substrate (context-dependent)</td>
<td>↑ membrane incorporation</td>
<td>G</td>
<td>Phospholipid composition shift</td>
<td>Changes membrane fluidity and eicosanoid substrate pool; time-dependent remodeling.</td>
</tr>
<tr>
<td>2</td>
<td>Eicosanoid balance (PGE1 vs AA-derived eicosanoids)</td>
<td>↔ / ↓ pro-inflammatory tone</td>
<td>↓ inflammation</td>
<td>G</td>
<td>Anti-inflammatory modulation</td>
<td>DGLA-derived PGE1 often anti-inflammatory; may counterbalance arachidonic acid metabolites.</td>
</tr>
<tr>
<td>3</td>
<td>ROS / Lipid peroxidation</td>
<td>↑ (PUFA-dependent; dose-dependent)</td>
<td>↔ / ↑ (high dose)</td>
<td>P/R</td>
<td>Lipid oxidative susceptibility</td>
<td>Highly unsaturated structure increases peroxidation potential; may sensitize tumors to oxidative stress.</td>
</tr>
<tr>
<td>4</td>
<td>NF-κB</td>
<td>↓ (context-dependent)</td>
<td>↓</td>
<td>R/G</td>
<td>Reduced inflammatory transcription</td>
<td>Often secondary to altered eicosanoid signaling.</td>
</tr>
<tr>
<td>5</td>
<td>PPAR (α/γ)</td>
<td>↑ (model-dependent)</td>
<td>↑</td>
<td>R/G</td>
<td>Lipid metabolic regulation</td>
<td>GLA and derivatives may activate PPAR pathways influencing lipid and glucose metabolism.</td>
</tr>
<tr>
<td>6</td>
<td>Apoptosis</td>
<td>↑ (high concentration only)</td>
<td>↔</td>
<td>R/G</td>
<td>Mitochondrial apoptosis (experimental)</td>
<td>Reported in certain tumor lines at supra-physiologic levels.</td>
</tr>
<tr>
<td>7</td>
<td>Ferroptosis</td>
<td>↑ (theoretical; PUFA-linked)</td>
<td>↔</td>
<td>R/G</td>
<td>Lipid peroxidation vulnerability</td>
<td>PUFA enrichment can enhance ferroptotic susceptibility depending on antioxidant context.</td>
</tr>
<tr>
<td>8</td>
<td>HIF-1α</td>
<td>↔ (limited evidence)</td>
<td>↔</td>
<td>G</td>
<td>Not primary axis</td>
<td>No consistent direct modulation reported.</td>
</tr>
<tr>
<td>9</td>
<td>NRF2</td>
<td>↔ / ↑ (adaptive; context-dependent)</td>
<td>↔</td>
<td>R/G</td>
<td>Redox-response adjustment</td>
<td>May activate antioxidant response secondary to lipid peroxidation stress.</td>
</tr>
<tr>
<td>10</td>
<td>Ca²⁺ signaling</td>
<td>↔ (membrane-dependent)</td>
<td>↔</td>
<td>P/R</td>
<td>Membrane microdomain modulation</td>
<td>Changes in lipid composition can subtly influence ion channel behavior.</td>
</tr>
<tr>
<td>11</td>
<td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td>
<td>↓ (constraint)</td>
<td>—</td>
<td>Context-dependent effects</td>
<td>Physiologic doses primarily anti-inflammatory; anti-cancer cytotoxicity not clinically established.</td>
</tr>
</table>
<p><b>TSF legend:</b><br>
P: 0–30 min (lipid oxidation events)<br>
R: 30 min–3 hr (acute signaling shifts)<br>
G: >3 hr (membrane remodeling and phenotype changes)</p>