Decoding Organ-Specific Vulnerability to Triptolide Toxicity: A Systems Toxicology Approach Targeting Glucose...

Area of Science:

• Pharmacology
• Computational Biology
• Toxicology

Background:

• Triptolide, a natural compound, has therapeutic potential but causes severe multi-organ toxicity.
• The precise mechanisms driving triptolide-induced toxicity are not fully understood.
• Understanding these mechanisms is crucial for clinical application and drug development.

Purpose of the Study:

• To elucidate the molecular mechanisms of triptolide-induced multi-organ toxicity.
• To utilize an integrative computational framework to identify toxicity pathways.
• To provide a basis for developing safer triptolide analogs.

Main Methods:

• Network pharmacology to identify toxicity targets.
• Mendelian randomization (MR) to assess causal links.
• Molecular docking and dynamics simulations for structural analysis.
• Single-cell RNA sequencing for cell-type-specific vulnerability.

Main Results:

• Identified 29 common toxicity targets across hepatic, renal, cardiac, and reproductive systems.
• Disruption of glycolysis and pentose phosphate pathways identified as a central mechanism.
• Dual toxicity model proposed: cellular energy crisis and oxidative redox imbalance.
• Confirmed stable interactions between triptolide and key metabolic enzymes (e.g., GCK, RPIA).

Conclusions:

• Triptolide-induced disruption of glucose homeostasis via direct enzyme interactions underlies its multi-organ toxicity.
• Integrative computational framework successfully bridged molecular interactions and organ pathology.
• Findings offer insights into pan-organ toxicity and guide the design of safer triptolide analogs.