Supplements & Compounds
Natural compounds and pharmaceutical options for HMGB1 modulation
This information is for educational purposes only. Always consult healthcare providers before starting any new supplement or intervention, especially if you have underlying health conditions or take medications.
Natural Compounds
The most potent natural HMGB1 inhibitor. EGCG induces HMGB1 aggregation near Cys106, triggering autophagy-mediated degradation. Effective even when taken 2-6 hours after inflammatory stimulus.
Dosage:
500-1,000 mg EGCG daily (or 2-3 cups green tea)
Safety:
Generally recognized as safe. High-dose supplements should be approached with caution in those with liver conditions.
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Inhibits NF-κB DNA-binding activity induced by HMGB1, prevents nuclear-to-cytoplasmic translocation, and blocks TLR4/MyD88/NF-κB inflammatory cascade.
Dosage:
250-1,000 mg daily
Safety:
Safe up to 1 gram daily for 12 weeks. May interact with antibiotics, cyclosporine, warfarin, and liver-metabolized drugs.
Food Sources:
Onions, berries, broccoli, kale (10-100 mg/day dietary intake)
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Alleviates HMGB1-mediated inflammation via TLR2/NF-κB pathway, reduces HMGB1 mRNA and protein expression. Targets SIRT1/PI3K/Akt/Nrf2 pathways.
Dosage:
500-2,000 mg daily
Bioavailability Enhancement:
MUST be taken with black pepper (piperine) for absorption. Poor aqueous solubility limits effectiveness without enhancement.
Safety:
Excellent safety in traditional dietary use and supplements at typical doses.
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Suppresses HMGB1 expression through upregulation of miR-149 and activates SIRT1, inhibiting HMGB1 nucleoplasmic translocation and extracellular release.
Dosage:
100-500 mg daily
Safety:
Safe up to 1,500 mg/day for 3 months. Higher doses (2,000-3,000 mg/day) may cause gastrointestinal upset. Avoid during pregnancy and breastfeeding.
Food Sources:
Red grapes, red wine, berries, peanuts
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Multiple active compounds (Rb1, Rb2, Rc, Rd, Rf, Rg1, Rh1, Rg5, Rk1) achieve SIRT1-mediated deacetylation of HMGB1. Ginsenoside Rg1 at 20 mg/kg provides neuroprotection and enhanced telomerase activity.
Dosage:
200-400 mg/day of extract
Safety:
Generally recognized as safe with over 2,000 years of traditional use. May interact with anticoagulants and affect blood sugar levels.
Directly binds HMGB1 A box and B box domains with favorable binding energy (ΔG = -7.0 kcal/mol). Blocks nucleocytoplasmic translocation and prevents extracellular release.
Safety Concerns:
Can cause hypertension, hypokalemia, and sodium retention at high doses. EU limits consumption to under 100 mg/day.
Contraindications:
Hypertension, heart failure, kidney disease, pregnancy. Electrolyte monitoring essential with long-term use.
Pharmaceutical Options
Widely prescribed type 2 diabetes medication that inhibits nuclear HMGB1 translocation to cytosol by directly binding the C-terminal domain. Decades of clinical use establish excellent safety profile.
Mechanism:
Retains HMGB1 in nucleus, down-regulates extracellular activity, inhibited HMGB1 release in LPS-treated cells
Status:
Immediately actionable repurposing candidate with established safety
Ester derivative of pyruvic acid with longer half-life. Blocks nuclear-to-cytoplasmic HMGB1 translocation and inhibits release. Possesses antioxidant properties limiting ROS damage.
Efficacy:
Animal dosing of 40-75 mg/kg IV/IP shows efficacy with significant post-insult delay tolerance. Well-tolerated in preclinical studies.
Applications:
Sepsis, inflammatory bowel disease, stroke, cancer, pancreatitis
Humanized antibodies (m2G7 clone) bind the A box domain, blocking both TLR4 and RAGE-mediated pathways. Wide therapeutic window—effective up to 24 hours post-insult.
Preclinical Success:
Improved survival in sepsis, prevented joint destruction in arthritis, protected against hepatotoxicity, enhanced muscle regeneration in aged mice
Status:
Humanized version ready for Phase 1 clinical trials
Synthetic serine protease inhibitor clinically approved for acute pancreatitis. Directly inhibits HMGB1 expression and release while blocking PAI-1 and PAR-2 activity.
Benefits:
Established safety profile from pancreatitis use provides clinical translation pathway
Supplement Recommendations Summary
- 1.Green Tea Extract (EGCG) - Excellent safety, highest potency (IC50 <1 μM)
- 2.Quercetin - Food-based, safe to 1g/day
- 3.Curcumin - Excellent safety with bioavailability enhancement (black pepper)
- 4.Resveratrol - Good safety profile, activates longevity pathways
- 5.Ginsenosides - Traditional longevity herb with 2,000+ years of use
- • Glycyrrhizin - Monitor blood pressure and potassium
- • Triptolide - Significant toxicity, requires medical supervision
- • High-dose supplements - Always consult healthcare provider first