Host-microbial co-mediated C-sulfonation constitutes a key metabolic detoxification pathway for celastrol, markedly improving its safety profile while maintaining therapeutic efficacy against rheumatoid arthritis.
Key Findings
Results
Celastrol undergoes extensive intestinal C-sulfonation in vivo to form a metabolite designated 2-phenolic-6-sulfo-celastrol (CELS), driven by a coordinated host-microbiota metabolic network.
The C-sulfonated metabolite was identified using ultra-high performance liquid chromatography-Orbitrap mass spectrometry (UHPLC-Orbitrap MS) and nuclear magnetic resonance (NMR) spectroscopy.
The C-sulfonation process involves both host and microbial contributions in a coordinated metabolic network.
Mechanistic investigations were performed using a microbial colonization model combined with pharmacological interventions.
Results
Host cysteine metabolism via cysteine dioxygenase contributes to sulfate (SO42-) production, which is a key step in the C-sulfonation of celastrol.
Cysteine dioxygenase is the host enzyme responsible for processing cysteine into sulfate.
This represents the host-side contribution to the coordinated host-microbiota metabolic network enabling C-sulfonation.
The host metabolic contribution was elucidated through mechanistic investigations combining microbial colonization models and pharmacological interventions.
Results
Gut microbial adenosine-5'-phosphosulfate reductase from Desulfovibrio piger reduces sulfate (SO42-) to sulfite (HSO3-), thereby enabling C-sulfonation of celastrol.
Desulfovibrio piger (D. piger) is the specific gut microbial species identified as contributing to the C-sulfonation process.
The microbial enzyme adenosine-5'-phosphosulfate reductase performs the reduction of SO42- to HSO3-.
This represents the microbiota-side contribution to the coordinated host-microbiota metabolic network.
Results
CELS showed markedly reduced hepatotoxicity compared to celastrol, as demonstrated by a 15.4-fold increase in IC50 value in L02 human hepatocytes.
IC50 for CELS in L02 cells was 30.38 μM compared to 1.85 μM for CEL, representing a 15.4-fold difference.
In a mouse survival study at 60 mg/kg for 7 days, CELS achieved 100% survival whereas CEL caused 80% mortality at the same dose.
Hepatotoxicity was evaluated in both mice and hepatocytes (L02 cells).
Results
CELS maintained anti-rheumatoid arthritis efficacy comparable to celastrol in a collagen-induced arthritis (CIA) mouse model.
CELS produced improvements in joint swelling, arthritis scores, and histopathological damage comparable to those of CEL in CIA mice.
Efficacy was evaluated using a collagen-induced arthritis (CIA) model.
The preservation of anti-RA efficacy despite reduced hepatotoxicity supports C-sulfonation as a detoxification rather than inactivation pathway.
Background
Celastrol's clinical translation is restricted by dose-dependent hepatotoxicity, which this study identifies as addressable through the C-sulfonation metabolic pathway.
Tripterygium wilfordii (Thunder God Vine) is a well-documented traditional medicinal herb widely used for treatment of rheumatoid arthritis.
Celastrol is one of its principal bioactive constituents responsible for anti-RA efficacy.
Clarifying the metabolic basis underlying both toxicity attenuation and efficacy preservation was identified as essential for the safe modernization and rational development of this ethnomedicine.
What This Means
This research investigates why a natural compound called celastrol, derived from the traditional Chinese medicinal plant Thunder God Vine, causes liver damage even though it is effective at treating rheumatoid arthritis. The study found that when celastrol enters the body, both the body's own metabolism and gut bacteria work together to chemically modify it through a process called C-sulfonation, converting it into a new form called CELS. This conversion involves the body producing sulfate through an enzyme called cysteine dioxygenase, and specific gut bacteria (Desulfovibrio piger) further processing that sulfate into a chemical form that can attach to celastrol and change its properties.
The transformed compound CELS was found to be dramatically safer than the original celastrol. In laboratory liver cells, CELS required 15.4 times higher concentrations to cause cell death compared to celastrol. Even more strikingly, when mice were given a high dose of 60 mg/kg for one week, all mice given CELS survived, while 80% of mice given the same dose of celastrol died. Despite being much safer, CELS still effectively reduced joint swelling, arthritis scores, and tissue damage in a mouse model of rheumatoid arthritis, performing comparably to the original celastrol.
This research suggests that the body naturally detoxifies celastrol through a partnership between its own metabolic processes and gut bacteria, and that understanding this process could help make Thunder God Vine-derived medicines safer for clinical use. The findings highlight the important role that gut microbiota play in determining both the safety and effectiveness of traditional herbal medicines, and suggest that CELS or strategies that promote its formation could be a pathway toward safer treatments for rheumatoid arthritis.
Tang D, Li X, Liu W, Lin Y, Xie C, Wen S, et al.. (2026). Host-microbial co-mediated C-sulfonation attenuates celastrol hepatotoxicity while preserving anti-rheumatic efficacy.. Journal of ethnopharmacology. https://doi.org/10.1016/j.jep.2026.121869