Description: <b>Hydrogen sulfide (H₂S)</b>, a gaseous signaling molecule, has been implicated in Alzheimer’s disease (AD) pathology with both neuroprotective and neurotoxic roles, depending on concentration, source, and context.<br>
- It was found that the endogenous H2S level in the brain of AD patients was significantly lower than that of normal people. <br>
-A cysteine-rich diet or supplementation with an appropriate amount of N-acetylcysteine is beneficial to the synthesis of H2S in the brain <br>
-Activates Nrf2, upregulates antioxidant genes Reduces oxidative stress, neuroprotective.<br>
-Inhibits NF-κB activation Suppresses inflammatory cytokines like TNF-α, IL-1β<br>
-Reduces Aβ aggregation and toxicity<br>
-Enhances cerebral blood flow<br>
<br>
**Accumulating evidence indicates that H2S exhibits bimodal modulation of cancer development. Thus, endogenous or low levels of exogenous H2S are thought to promote cancer, whereas high doses of exogenous H2S suppress tumor proliferation.**<br>
<br>
<p><b>Hydrogen sulfide (H₂S)</b> — a small, membrane-permeable gaseous signaling molecule and endogenous gasotransmitter produced principally through cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE/CTH), and 3-mercaptopyruvate sulfurtransferase (3-MST/MPST). It functions as a redox and metabolic signaling mediator, notably through protein persulfidation, modulation of mitochondrial electron transport, vascular signaling, and stress-response pathways. H₂S has a strongly biphasic biological profile: low physiologic concentrations can promote mitochondrial bioenergetics, cytoprotection, proliferation, and angiogenesis, whereas sufficiently high concentrations inhibit mitochondrial Complex IV and can cause energetic collapse and cell death. In cancer this creates an important therapeutic paradox because many tumors exploit increased endogenous H₂S production, while high-output or tumor-targeted H₂S donors are being investigated experimentally as anticancer agents.</p>
<p><b>Primary mechanisms (ranked):</b></p>
<ol>
<li>Protein persulfidation of cysteine residues, altering enzyme activity, signaling, stress responses, DNA repair, and metabolism.</li>
<li>Biphasic mitochondrial regulation: low H₂S can support electron transport and ATP production, whereas high H₂S inhibits cytochrome-c oxidase / mitochondrial Complex IV.</li>
<li>CBS/CSE/3-MST-derived endogenous H₂S can support tumor-cell bioenergetics, proliferation, survival, and angiogenesis.</li>
<li>Redox regulation through glutathione, reactive oxygen species buffering, and Keap1 persulfidation with NRF2 activation.</li>
<li>Modulation of mitochondrial and nuclear DNA repair, including persulfidation-dependent mitochondrial DNA repair mechanisms.</li>
<li>Vascular signaling and vasodilation, including interactions with nitric oxide signaling that can promote tumor perfusion and angiogenesis.</li>
<li>At sufficiently high or rapidly delivered concentrations, mitochondrial respiratory inhibition, ATP depletion, oxidative/metabolic stress, and apoptosis or other forms of cancer-cell death.</li>
<li>Modulation of inflammatory signaling including NF-κB and NLRP3, generally anti-inflammatory under physiologic/cytoprotective conditions but strongly context-dependent in tumors.</li>
</ol>
<p><b>Bioavailability / PK relevance:</b> Free H₂S is highly diffusible but extremely short-lived in biological systems because it is rapidly oxidized, scavenged, bound, or incorporated into reactive sulfur species. Experimental studies therefore commonly use NaHS, Na₂S, GYY4137, AP39, SG1002, or other H₂S-releasing compounds rather than administering gaseous H₂S systemically. Release rate, intracellular localization, oxygen tension, sulfide oxidation capacity, and tissue targeting can substantially change biological effects.</p>
<p><b>In-vitro vs systemic exposure relevance:</b> Concentration is critical. Bolus sulfide salts can transiently produce H₂S concentrations considerably higher than sustained physiologic exposure and therefore may cause mitochondrial inhibition that does not represent endogenous H₂S signaling. Results obtained with high-concentration NaHS or Na₂S should not be interpreted as equivalent to physiologic endogenous H₂S or slow-release donors. Tumor-targeted and mitochondria-targeted donors are intended to overcome this exposure problem.</p>
<p><b>Clinical evidence status:</b> <b>Preclinical for cancer therapy.</b> Tumor H₂S metabolism is well supported mechanistically in experimental cancer models, but H₂S administration is not an established cancer treatment. H₂S donors and H₂S-generating systems remain investigational. SG1002 has undergone small Phase I human studies primarily in cardiovascular disease, not cancer. No H₂S donor has established clinical efficacy for cancer, and inhaled/free H₂S is a toxic respiratory and mitochondrial poison at sufficiently high exposure.</p>
<h3>Hydrogen Sulfide Cancer-Relevant Mechanisms</h3>
<table>
<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>CBS CSE 3-MST H₂S signaling</td>
<td>↑ frequently in selected tumors</td>
<td>↔ physiologic homeostasis</td>
<td>G</td>
<td>↑ proliferation and survival</td>
<td>Many cancers increase one or more H₂S-generating enzymes. The dominant enzyme is tumor-type dependent; CBS is particularly established in colorectal and ovarian models, while 3-MST and CSE contribute in other cancers.</td>
</tr>
<tr>
<td>2</td>
<td>Mitochondrial electron transport and Complex IV</td>
<td>↑ at low H₂S; ↓ at high H₂S</td>
<td>↑ at low H₂S; ↓ at high H₂S</td>
<td>P</td>
<td>Biphasic bioenergetic regulation</td>
<td>Low endogenous H₂S can act as a mitochondrial electron source and support ATP production. High sulfide concentrations inhibit cytochrome-c oxidase and suppress oxidative phosphorylation (dose-dependent).</td>
</tr>
<tr>
<td>3</td>
<td>Protein persulfidation</td>
<td>↑</td>
<td>↑</td>
<td>P–R</td>
<td>Post-translational signaling regulation</td>
<td>A major signaling mechanism of H₂S and reactive sulfur species. Effects depend on the protein modified and cellular redox environment.</td>
</tr>
<tr>
<td>4</td>
<td>Mitochondrial DNA repair</td>
<td>↑</td>
<td>↔ or ↑</td>
<td>R–G</td>
<td>↑ stress resistance and survival</td>
<td>In lung adenocarcinoma, endogenous H₂S supports mitochondrial DNA repair including persulfidation of EXOG and stabilization of mitochondrial DNA-repair complexes.</td>
</tr>
<tr>
<td>5</td>
<td>Angiogenesis and tumor perfusion</td>
<td>↑</td>
<td>↑ vascular relaxation</td>
<td>R–G</td>
<td>↑ blood flow and angiogenic signaling</td>
<td>Endogenous tumor-derived H₂S can stimulate vascular responses and tumor angiogenesis; interactions with NO signaling are important.</td>
</tr>
<tr>
<td>6</td>
<td>ROS and redox buffering</td>
<td>↓ at physiologic levels; ↑ possible at cytotoxic exposure</td>
<td>↓</td>
<td>P–R</td>
<td>Redox homeostasis</td>
<td>H₂S can increase antioxidant capacity and limit oxidative damage, but high concentrations that disrupt mitochondria can instead promote metabolic and oxidative stress (dose-dependent).</td>
</tr>
<tr>
<td>7</td>
<td>Keap1 NRF2 antioxidant signaling</td>
<td>↑ (context-dependent)</td>
<td>↑</td>
<td>R</td>
<td>↑ cytoprotection and antioxidant transcription</td>
<td>Persulfidation of Keap1 can release NRF2 and increase antioxidant defenses. This is generally cytoprotective and therefore can potentially protect tumor cells as well as normal tissue.</td>
</tr>
<tr>
<td>8</td>
<td>Apoptosis</td>
<td>↓ at low H₂S; ↑ at high H₂S</td>
<td>↓ at physiologic cytoprotective levels</td>
<td>R–G</td>
<td>Biphasic cell-survival control</td>
<td>Endogenous or low donor exposure often suppresses apoptosis. High-output or targeted H₂S delivery may induce mitochondrial dysfunction and cancer-cell death (dose-dependent).</td>
</tr>
<tr>
<td>9</td>
<td>NF-κB inflammatory signaling</td>
<td>↓ or mixed</td>
<td>↓</td>
<td>R</td>
<td>Anti-inflammatory signaling</td>
<td>H₂S can suppress NF-κB-dependent inflammatory signaling, but effects are cell-, dose-, and disease-context dependent.</td>
</tr>
<tr>
<td>10</td>
<td>NLRP3 inflammasome</td>
<td>↓ or mixed</td>
<td>↓</td>
<td>R–G</td>
<td>↓ inflammatory activation</td>
<td>Generally reported as inhibitory in inflammatory models; its net contribution to tumor immunity is context-dependent.</td>
</tr>
<tr>
<td>11</td>
<td>Chemosensitivity</td>
<td>↓ with endogenous H₂S; ↑ when H₂S synthesis is inhibited</td>
<td>↔</td>
<td>G</td>
<td>Modulation of treatment resistance</td>
<td>Endogenous H₂S can support DNA repair and bioenergetics in some tumors. CBS/CSE/3-MST inhibition can therefore increase chemotherapy sensitivity in experimental models; this does not imply that supplemental H₂S is a chemosensitizer.</td>
</tr>
<tr>
<td>12</td>
<td>High-output H₂S cytotoxicity</td>
<td>↑ cell death</td>
<td>↑ toxicity at sufficient exposure</td>
<td>P–R</td>
<td>Complex IV inhibition and energetic collapse</td>
<td>The anticancer concept requires controlled or tumor-selective delivery because the same mechanism can injure normal cells and becomes systemically toxic.</td>
</tr>
<tr>
<td>13</td>
<td>Clinical Translation Constraint</td>
<td>Context-dependent</td>
<td>Dose-limited</td>
<td>P–G</td>
<td>Delivery and therapeutic-window limitation</td>
<td>Rapid sulfide metabolism, narrow concentration-dependent transition between signaling and toxicity, donor-specific PK, tissue oxygenation, tumor heterogeneity, and lack of cancer efficacy trials currently limit translation.</td>
</tr>
</tbody>
</table>
<p><b>TSF:</b> P: 0–30 min R: 30 min–3 hr G: >3 hr</p>
<br><br>
<p><b>Hydrogen sulfide and Alzheimer’s disease:</b> H₂S is an endogenous neuromodulatory gasotransmitter with substantial preclinical evidence for neuroprotective effects relevant to Alzheimer’s disease. Experimental H₂S replacement or donor treatment can suppress tau hyperphosphorylation, reduce amyloidogenic processing, decrease oxidative and inflammatory injury, and improve cognition in animal models. A particularly well-supported mechanism is persulfidation of GSK3β, which decreases its kinase activity and reduces pathological tau phosphorylation. H₂S biology is nevertheless concentration-dependent, and excessive H₂S can inhibit mitochondrial Complex IV and become neurotoxic.</p>
<p><b>Clinical evidence status:</b> <b>Preclinical.</b> Cell and transgenic-animal studies support disease-modifying mechanisms, but there is no established H₂S donor therapy for Alzheimer’s disease and no evidence from therapeutic RCTs demonstrating clinical efficacy. Human studies have primarily examined H₂S as a biomarker rather than treatment.</p>
<h3>Hydrogen Sulfide Alzheimer-Relevant Mechanisms</h3>
<table>
<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>GSK3β persulfidation and Tau phosphorylation</td>
<td>GSK3β ↓; Tau phosphorylation ↓</td>
<td>R–G</td>
<td>↓ pathological Tau signaling</td>
<td>H₂S-dependent persulfidation of GSK3β suppresses kinase activity; loss of this modification has been demonstrated in AD-related experimental systems.</td>
</tr>
<tr>
<td>2</td>
<td>Amyloid beta production and accumulation</td>
<td>↓</td>
<td>G</td>
<td>↓ amyloid burden</td>
<td>H₂S donors reduced Aβ generation and accumulation in APP/PS1 and related experimental models.</td>
</tr>
<tr>
<td>3</td>
<td>BACE1 and amyloidogenic APP processing</td>
<td>↓</td>
<td>G</td>
<td>↓ Aβ production</td>
<td>Experimental evidence indicates suppression of BACE1 and PS1-associated amyloidogenic processing.</td>
</tr>
<tr>
<td>4</td>
<td>Oxidative stress and ROS</td>
<td>↓</td>
<td>P–R</td>
<td>Neuroprotection</td>
<td>Physiologic H₂S signaling supports glutathione/redox defense and limits oxidative injury.</td>
</tr>
<tr>
<td>5</td>
<td>Keap1 NRF2 antioxidant signaling</td>
<td>↑</td>
<td>R</td>
<td>↑ antioxidant response</td>
<td>Keap1 persulfidation can promote NRF2 activation and downstream antioxidant gene expression.</td>
</tr>
<tr>
<td>6</td>
<td>Neuroinflammation and NF-κB</td>
<td>↓</td>
<td>R–G</td>
<td>↓ inflammatory injury</td>
<td>H₂S suppresses inflammatory cytokine signaling in multiple neural and non-neural experimental systems.</td>
</tr>
<tr>
<td>7</td>
<td>NLRP3 inflammasome</td>
<td>↓</td>
<td>R–G</td>
<td>↓ neuroinflammatory activation</td>
<td>Consistent with the broader anti-inflammatory actions of physiologic H₂S, although the effect varies with model and dose.</td>
</tr>
<tr>
<td>8</td>
<td>Mitochondrial function</td>
<td>↑ at low H₂S; ↓ at high H₂S</td>
<td>P</td>
<td>Biphasic mitochondrial regulation</td>
<td>Physiologic concentrations support mitochondrial function; excessive sulfide inhibits Complex IV and becomes neurotoxic (dose-dependent).</td>
</tr>
<tr>
<td>9</td>
<td>Cerebral blood flow and vascular signaling</td>
<td>↑</td>
<td>P–R</td>
<td>↑ neurovascular support</td>
<td>Vasodilatory H₂S signaling may improve cerebral perfusion in experimental models.</td>
</tr>
<tr>
<td>10</td>
<td>Neuronal apoptosis</td>
<td>↓ at protective concentrations</td>
<td>R–G</td>
<td>↑ neuronal survival</td>
<td>H₂S donors reduce Aβ-associated and oxidative-stress-associated neuronal apoptosis in preclinical models.</td>
</tr>
<tr>
<td>11</td>
<td>Clinical Translation Constraint</td>
<td>Context-dependent</td>
<td>P–G</td>
<td>Unproven human therapeutic efficacy</td>
<td>Optimal brain H₂S exposure is unknown; free H₂S has rapid PK and substantial toxicity at high concentrations. No therapeutic AD RCT establishes efficacy or an appropriate clinical dose.</td>
</tr>
</tbody>
</table>
<p><b>TSF:</b> P: 0–30 min R: 30 min–3 hr G: >3 hr</p>