Description: <p><b>Auranofin (AF)</b> — oral gold(I) small-molecule drug (originally for rheumatoid arthritis; repurposing interest in oncology/inflammation). Key sources: PK/absorption data and serum/plasma gold levels from clinical pharmacokinetics and Phase I studies; oncology mechanisms largely via thioredoxin reductase (TXNRD/TrxR) targeting and redox stress. Its structure features a gold atom coordinated with triethylphosphine and a thiolate ligand derived from a sugar (often referred to as a thiosugar)<br><br>
<b>Primary mechanisms (conceptual rank)</b><br>
1) TXNRD1/TrxR inhibition → collapse of thioredoxin redox buffering (rapid) :contentReference[oaicite:1]{index=1}<br>
2) ROS↑ / redox stress → apoptosis/regulated death; can engage ferroptosis in some models :contentReference[oaicite:2]{index=2}<br>
3) Proteostasis stress (proteasome involvement) / paraptosis in selected contexts (model-dependent) :contentReference[oaicite:3]{index=3}<br>
4) Metabolic stress: glycolysis/ATP disruption reported in some cancer models (context-dependent) :contentReference[oaicite:4]{index=4}<br><br>
<b>Bioavailability / PK relevance</b><br>
Oral absorption of auranofin is limited (~20–30% absorbed reported in classic PK summaries); gold is highly protein-bound with long terminal half-life, so exposure depends strongly on dosing duration. :contentReference[oaicite:5]{index=5}<br><br>
<b>In-vitro vs systemic exposure</b><br>
Many oncology in-vitro studies use low–mid µM AF; human plasma gold concentrations on 6 mg/day for 7 days were reported ~0.2 µg/mL (~1.0 µM gold), implying some in-vitro ranges overlap systemic exposure but higher in-vitro doses may exceed typical oral steady exposures (especially short-course). :contentReference[oaicite:6]{index=6}<br><br>
<b>Clinical evidence status (cancer)</b><br>
Predominantly preclinical + early-phase/repurposing trials (multiple oncology trials registered/ongoing; generally not established as standard-of-care anticancer therapy). :contentReference[oaicite:7]{index=7}</p>
<br>
Pathways:<br>
1.Thioredoxin Reductase (TrxR) Inhibition.<br>
- Most widely recognized for potently inhibiting TrxR.<br>
2.Induction of Reactive Oxygen Species (ROS) and Oxidative Stress.<br>
3.MMP depolarization, release of cytochrome c <br>
4.Endoplasmic Reticulum (ER) Stress and Unfolded Protein Response (UPR)<br>
5.Inhibition of Pro-survival Pathways (e.g., NF-κB Signaling)<br>
<br>
-ic50 for cancer typically 1-3uM, normal cell 5-10uM or higher.<br>
-Several studies animal testing antitumor efficacy have used doses in the region of 5–8 mg/kg via intraperitoneal injection or oral administration.<br>
<br>
-Auranofin’s anticancer activity is often linked to its inhibition of thioredoxin reductase, leading to increased oxidative stress.<br>
<h3>Auranofin (AF) — ranked mechanistic axes (Cancer vs Normal)</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>TXNRD1 / Thioredoxin system (TrxR)</td>
<td>↓ (primary)</td>
<td>↓ (primary)</td>
<td>P→R</td>
<td>Redox-buffer collapse; stress sensitization</td>
<td>Cancer reliance on antioxidant buffering can create vulnerability; mechanism is not tumor-selective by itself. :contentReference[oaicite:8]{index=8}</td>
</tr>
<tr>
<td>2</td>
<td>ROS / Redox stress</td>
<td>↑ (often primary downstream)</td>
<td>↑ (dose-/context-dependent)</td>
<td>P→R</td>
<td>Oxidative stress signaling → cell-death programs</td>
<td>ROS-mediated effects are frequently NAC-reversible in models (supports redox causality). :contentReference[oaicite:9]{index=9}</td>
</tr>
<tr>
<td>3</td>
<td>Ferroptosis axis (lipid peroxidation-dependent death)</td>
<td>↑ (model-dependent)</td>
<td>↔/↑ (high concentration or stress-prone tissues)</td>
<td>R→G</td>
<td>Regulated death component in some tumor lines</td>
<td>Reported as a component of AF-induced death in specific cancer models; not universal. :contentReference[oaicite:10]{index=10}</td>
</tr>
<tr>
<td>4</td>
<td>NRF2 antioxidant response</td>
<td>↑ (adaptive; resistance role)</td>
<td>↑ (protective)</td>
<td>R→G</td>
<td>Stress-response transcriptional adaptation</td>
<td>NRF2 induction can be protective in normal cells but can also support tumor survival/therapy resistance (context-dependent). (Inference from redox-stress mechanism + TrxR targeting.) :contentReference[oaicite:11]{index=11}</td>
</tr>
<tr>
<td>5</td>
<td>Proteostasis / Proteasome involvement</td>
<td>↓ (model-dependent)</td>
<td>↔/↓ (high concentration only)</td>
<td>R→G</td>
<td>ER/protein-folding stress; paraptosis in some models</td>
<td>Breast cancer report: dual TrxR + proteasome inhibition required for paraptosis (not necessarily generalizable). :contentReference[oaicite:12]{index=12}</td>
</tr>
<tr>
<td>6</td>
<td>Mitochondrial function (Δψm, ATP) / mitophagy</td>
<td>↓ (stress-dependent)</td>
<td>↓ (dose-dependent)</td>
<td>R</td>
<td>Energy crisis; organelle stress signaling</td>
<td>Mitochondrial dysfunction + oxidative stress have been observed in non-cancer retinal cells; normal tissue liability depends on exposure and susceptibility. :contentReference[oaicite:13]{index=13}</td>
</tr>
<tr>
<td>7</td>
<td>Ca²⁺ signaling (ER/mitochondrial stress coupling)</td>
<td>↑/↔ (secondary; context-dependent)</td>
<td>↑/↔ (secondary; context-dependent)</td>
<td>R</td>
<td>Stress amplification; apoptosis susceptibility</td>
<td>Often downstream of redox + mitochondrial/ER perturbation; include when apoptosis/ER-stress phenotypes are reported for the specific model.</td>
</tr>
<tr>
<td>8</td>
<td>Glycolysis / ATP production</td>
<td>↓ (context-dependent)</td>
<td>↔/↓ (high concentration only)</td>
<td>R</td>
<td>Metabolic stress; reduces stem-like fractions in some models</td>
<td>Reported glycolysis inhibition with associated ATP depletion in lung cancer stem-like side-population context. :contentReference[oaicite:14]{index=14}</td>
</tr>
<tr>
<td>9</td>
<td>HIF-1α (hypoxia/Warburg coupling)</td>
<td>↔ (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Context marker rather than core target</td>
<td>Not a primary AF axis; evaluate case-by-case when hypoxia/redox/HIF programs are explicitly measured in the study set.</td>
</tr>
<tr>
<td>10</td>
<td><i>Clinical Translation Constraint</i></td>
<td>↔</td>
<td>↔</td>
<td>—</td>
<td>Exposure + tolerability + selectivity</td>
<td>Oral absorption is limited (~20–30%); plasma gold ~1 µM after short-course 6 mg/day dosing reported; many in-vitro studies use overlapping-to-higher µM ranges; oncology use remains largely investigational/early-phase. :contentReference[oaicite:15]{index=15}</td>
</tr>
</table>
<p><b>TSF legend:</b> P: 0–30 min (primary/rapid effects; direct enzyme/redox interactions) | R: 30 min–3 hr (acute signaling + stress responses) | G: >3 hr (gene-regulatory adaptation; phenotype outcomes)</p>