Description: <p><b>Docosahexaenoic Acid (DHA)</b> = long-chain omega-3 polyunsaturated fatty acid (22:6n-3); major structural lipid of neuronal membranes and retina; dietary sources: fatty fish (salmon, sardine), algae oils; often combined with EPA in supplements.<br>
<b>Primary mechanisms (conceptual rank):</b><br>
1) Membrane incorporation → alters fluidity, lipid rafts, receptor signaling domains.<br>
2) Pro-resolving lipid mediator precursor (resolvins, protectins, maresins) → inflammation resolution.<br>
3) Mitochondrial modulation → can ↑ lipid-ROS in cancer (pro-ferroptotic bias) yet stabilize neuronal bioenergetics.<br>
4) Synaptic function / neurogenesis support (BDNF-linked, model-dependent).<br>
<b>PK / bioavailability:</b> absorbed with dietary fat; re-esterified into phospholipids; crosses BBB; brain incorporation is gradual (weeks–months); higher RBC-DHA correlates with intake.<br>
<b>In-vitro vs systemic exposure:</b> many cancer studies use ≥25–100 µM free DHA; achievable plasma levels from oral dosing are typically lower and largely esterified, limiting direct comparability.<br>
<b>Clinical evidence status:</b> strong cardiometabolic data; oncology evidence largely preclinical/adjunct; AD/MCI data mixed but mechanistically coherent.</p>
<b>Omega-3 fatty acid</b> found in cold-water fish and some supplements.<br>
– DHA is a major structural component of cell membranes in the brain, retina, and other tissues and plays a critical role in neural function and development.<br>
<br>
Role in Cancer<br>
<br>
Anti-Inflammatory Effects: – A reduction in chronic inflammation<br>
Modulation of Cell Proliferation and Apoptosis<br>
–Omega-3 fatty acids appear to influence cell cycle regulation and apoptosis (programmed cell death). By enhancing apoptosis and inhibiting proliferation, these agents may limit the growth of cancer cells.<br>
Alteration of Membrane Composition and Signaling<br>
–May affect processes such as angiogenesis (formation of new blood vessels), cell adhesion, and metastasis in cancer cells.<br>
Impact on Oxidative Stress<br>
–Although omega-3 fatty acids are prone to oxidation, their metabolites can have antioxidant properties. Balancing oxidation and antioxidant defenses is important in preventing oxidative stress—a known contributor to DNA damage and cancer development.<br>
Anti-Angiogenic Effects<br>
– Some studies have shown that EPA and DHA can inhibit angiogenesis.<br>
<br>
<h3>Docosahexaenoic Acid (DHA) — Cancer-Relevant Pathways</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>Lipid peroxidation / Ferroptosis axis</td>
<td>↑ (pro-ferroptotic bias; dose-dependent)</td>
<td>↔ / mild ↑ (buffered)</td>
<td>P→R</td>
<td>PUFA enrichment → lipid-ROS susceptibility</td>
<td>DHA increases membrane PUFA content; tumors with weak GPX4 defenses more vulnerable (model-dependent).</td>
</tr>
<tr>
<td>2</td>
<td>ROS tone</td>
<td>↑ (high concentration only)</td>
<td>↔</td>
<td>P→R</td>
<td>Oxidative stress induction</td>
<td>Free DHA oxidation can elevate ROS in cancer; physiologic dosing less pronounced.</td>
</tr>
<tr>
<td>3</td>
<td>Inflammation (NF-κB / COX-2)</td>
<td>↓</td>
<td>↓</td>
<td>R→G</td>
<td>Anti-inflammatory / pro-resolving</td>
<td>Via resolvins/protectins; may reduce tumor-promoting inflammation.</td>
</tr>
<tr>
<td>4</td>
<td>Membrane signaling / lipid rafts</td>
<td>↓ oncogenic signaling (context-dependent)</td>
<td>Modulates receptor clustering</td>
<td>R→G</td>
<td>Alters RTK / Akt pathway localization</td>
<td>Changes raft composition; can dampen EGFR/PI3K signaling (model-dependent).</td>
</tr>
<tr>
<td>5</td>
<td>HIF-1α / hypoxia signaling</td>
<td>↓ (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Reduced hypoxic adaptation</td>
<td>Reported in some solid tumor models; not universal.</td>
</tr>
<tr>
<td>6</td>
<td>NRF2 axis</td>
<td>↔ / ↑ (adaptive)</td>
<td>↑ (protective)</td>
<td>G</td>
<td>Antioxidant adaptation</td>
<td>Lipid peroxidation may secondarily activate NRF2; can limit ferroptosis in resistant tumors.</td>
</tr>
<tr>
<td>7</td>
<td>Ca²⁺ signaling / ER stress</td>
<td>↑ (high concentration only)</td>
<td>↔</td>
<td>R</td>
<td>Stress-induced apoptosis (select models)</td>
<td>High free DHA can perturb ER Ca²⁺ handling; typically supra-physiologic exposure.</td>
</tr>
<tr>
<td>8</td>
<td>Clinical Translation Constraint</td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>Adjunct potential</td>
<td>In-vitro dosing often exceeds systemic free DHA; best studied as chemo-sensitizing adjunct rather than monotherapy.</td>
</tr>
</table>
<p><b>TSF Legend:</b> P: 0–30 min | R: 30 min–3 hr | G: >3 hr</p>
<br>
<h3>Docosahexaenoic Acid (DHA) — Alzheimer’s Disease–Relevant Axes</h3>
<table>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cells (neurons/glia)</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Membrane fluidity / synaptic integrity</td>
<td>↑</td>
<td>G</td>
<td>Synaptic stabilization</td>
<td>DHA major neuronal phospholipid; supports dendritic spine density and neurotransmission.</td>
</tr>
<tr>
<td>2</td>
<td>Neuroinflammation resolution</td>
<td>↓ (pro-resolving)</td>
<td>R→G</td>
<td>Resolvins / protectins</td>
<td>Promotes resolution rather than suppression of inflammation; relevant in microglial activation.</td>
</tr>
<tr>
<td>3</td>
<td>Mitochondrial efficiency</td>
<td>↑ (stabilizing)</td>
<td>R→G</td>
<td>Bioenergetic support</td>
<td>Improves membrane dynamics of mitochondria; may enhance ATP coupling (model-dependent).</td>
</tr>
<tr>
<td>4</td>
<td>Aβ processing / amyloid burden</td>
<td>↓ (preclinical)</td>
<td>G</td>
<td>Modulates APP cleavage</td>
<td>Animal/cell data supportive; human trials mixed, stronger in early/MCI stages.</td>
</tr>
<tr>
<td>5</td>
<td>BDNF / neuroplasticity</td>
<td>↑ (model-dependent)</td>
<td>G</td>
<td>Neurotrophic support</td>
<td>Reported increase in BDNF signaling in experimental models.</td>
</tr>
<tr>
<td>6</td>
<td>Clinical Translation Constraint</td>
<td>—</td>
<td>—</td>
<td>Stage-dependent benefit</td>
<td>MCI/early AD may benefit; established AD shows limited cognitive reversal in RCTs; incorporation requires sustained intake.</td>
</tr>
</table>
<p><b>TSF Legend:</b> P: 0–30 min | R: 30 min–3 hr | G: >3 hr</p>