# Celastrol
**Celastrol** (also called tripterine) is a quinone-methide pentacyclic triterpenoid of molecular formula C29H38O4, isolated in 1936 from the root bark of the medicinal vine *Tripterygium wilfordii* Hook. f., known in Chinese medicine as Lei Gong Teng, the Thunder God Vine.[1](https://pubchem.ncbi.nlm.nih.gov/compound/Celastrol) • [2](https://pubmed.ncbi.nlm.nih.gov/33174200/) It shows anti-inflammatory, anticancer, and antiobesity activity in preclinical models, and in 2007 *Cell* magazine listed it among five natural products considered most likely to be developed into modern pharmaceuticals.[3](https://pubs.rsc.org/en/content/articlehtml/2024/ra/d4ra07602h) Its development as a drug has been limited by poor water solubility, low oral bioavailability, and a narrow therapeutic window.[2](https://pubmed.ncbi.nlm.nih.gov/33174200/)
| Key fact | Detail |
|---|---|
| Chemical class | Quinone-methide triterpenoid (friedelane-type pentacyclic triterpenoid), C29H38O4, molecular weight 450.6 g/mol, XLogP 5.9[1](https://pubchem.ncbi.nlm.nih.gov/compound/Celastrol) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10038137/) |
| Natural source | Root bark of *Tripterygium wilfordii* (Celastraceae); first isolated in 1936[2](https://pubmed.ncbi.nlm.nih.gov/33174200/) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10038137/) |
| Key reactivity | The quinone methide spanning rings A and B is a Michael acceptor that reacts with the thiolate form of cysteine residues in proteins[5](https://www.mdpi.com/1420-3049/31/20/3641) |
| Molecular targets | Disrupts the Hsp90–Cdc37 chaperone complex; activates heat shock factor 1; chemical proteomics in HeLa cells identified more than 60 target proteins[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC2790967/) • [5](https://www.mdpi.com/1420-3049/31/20/3641) • [7](https://pubs.rsc.org/en/content/articlehtml/2017/mb/c6mb00691d) |
| Antiobesity effect | Up to 45% weight loss in hyperleptinemic diet-induced obese mice by increasing leptin sensitivity; ineffective in leptin-deficient (ob/ob) and leptin-receptor-deficient (db/db) mice[8](https://pubmed.ncbi.nlm.nih.gov/26000480/) |
| Development barriers | Poor water solubility (about 0.014 mg/mL, roughly 30 μM), low oral bioavailability, short plasma half-life, and dose-dependent toxicity[9](https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1137289/full) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC12420926/) |
| Clinical status | No clinical trials in humans for cancer have been conducted; clinical work overall remains at an early stage[11](https://www.sciencedirect.com/science/article/pii/S0304383521004274) • [12](https://pmc.ncbi.nlm.nih.gov/articles/PMC12380071/) |
## Chemistry and natural occurrence
Celastrol is a friedelane-type pentacyclic triterpenoid bearing a carboxylic acid, a hydroxyl group, and a quinone methide system across rings A and B.[1](https://pubchem.ncbi.nlm.nih.gov/compound/Celastrol) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10038137/) It is one of the most abundant bioactive components of *T. wilfordii* root bark, a plant used in traditional Chinese medicine for more than two thousand years to treat inflammatory and autoimmune conditions such as rheumatoid arthritis, gout, and psoriasis.[3](https://pubs.rsc.org/en/content/articlehtml/2024/ra/d4ra07602h) • [5](https://www.mdpi.com/1420-3049/31/20/3641) The compound is obtained mainly by extraction from roots and root bark in low yield, and supply is limited by the slow growth and restricted distribution of the source plant.[5](https://www.mdpi.com/1420-3049/31/20/3641)
**Reactive pharmacophore.** The quinone methide moiety is a [Michael acceptor](https://www.edgepedia.org/michael-acceptor) that reacts with the thiolate form of cysteine residues in proteins, and every attempt to define the pharmacophore has converged on this structural feature.[5](https://www.mdpi.com/1420-3049/31/20/3641) The resulting covalent adducts are reversible rather than permanent: work using the nuclear receptor Nur77 as a model target showed that celastrol is first positioned by noncovalent contacts that orient the quinone methide next to the reactive cysteine.[5](https://www.mdpi.com/1420-3049/31/20/3641) This promiscuous, reversible covalent alkylation of protein thiols explains both the compound's diverse [biological effects](https://www.edgepedia.org/biological-effect) and the difficulty of attributing them to a single receptor.[7](https://pubs.rsc.org/en/content/articlehtml/2017/mb/c6mb00691d)
## Mechanisms of action
**Hsp90 pathway.** Celastrol disrupts formation of the complex between the molecular chaperone Hsp90 and its cochaperone [Cdc37](https://www.edgepedia.org/cdc37), which loads protein kinase clients onto Hsp90, and it inhibits Hsp90 ATPase activity without blocking ATP binding; classical Hsp90 inhibitors such as geldanamycin do not disrupt this interaction.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC2790967/) Proteolytic fingerprinting localized the interaction to the Hsp90 C-terminal domain, indicating allosteric rather than competitive regulation, and solution NMR work placed a binding event on Cdc37 itself through cysteine-dependent inactivation.[5](https://www.mdpi.com/1420-3049/31/20/3641) In parallel, celastrol activates heat shock factor 1 (HSF1), inducing expression of Hsp70, Hsp40, and Hsp27 with kinetics resembling heat stress.[5](https://www.mdpi.com/1420-3049/31/20/3641)
**Proteome-wide targeting.** Because celastrol reacts covalently and reversibly with protein thiols, competitive chemical proteomics using a cysteine-targeted probe identified more than 60 target proteins in HeLa cells, including [GSTO1](https://www.edgepedia.org/gsto1) and protein disulfide isomerases.[7](https://pubs.rsc.org/en/content/articlehtml/2017/mb/c6mb00691d) A degradation-based protein profiling strategy combining PROTAC technology with quantitative proteomics subsequently validated IKKβ and PI3Kα as known targets and proposed checkpoint kinase 1 (CHK1) and O-GlcNAcase (OGA) as potential new ones.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC11220716/) Reported signaling pathways affected by celastrol include NF-κB, PI3K/AKT, STAT3, JAK/STAT, and MAPK.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC11220716/) • [9](https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1137289/full)
## Antiobesity activity
A 2015 *Cell* study reported that celastrol suppresses food intake, blocks the reduction of energy expenditure, and produces up to 45% weight loss in hyperleptinemic diet-induced obese mice by increasing leptin sensitivity, while it is ineffective in leptin-deficient (ob/ob) and leptin-receptor-deficient (db/db) mouse models.[8](https://pubmed.ncbi.nlm.nih.gov/26000480/) A companion review described celastrol as a true leptin sensitizer, effective by both oral and intraperitoneal administration.[14](https://www.nature.com/articles/nrendo.2015.94) In 2019, interleukin-1 receptor 1 (IL1R1) was identified as a mediator of celastrol's leptin-sensitizing and antiobesity effects through analysis of the hypothalamic transcriptome of treated mice.[15](https://www.nature.com/articles/s41591-019-0358-x) Celastrol also protects against metabolic dysfunction through activation of an HSF1–PGC1α transcriptional axis, associated with enhanced energy expenditure and improved mitochondrial function in fat and muscle.[16](https://pubmed.ncbi.nlm.nih.gov/26344102/)
## Biosynthesis and total synthesis
**Biosynthetic route.** Celastrol is synthesized from 2,3-oxidosqualene, which [oxidosqualene cyclases](https://www.edgepedia.org/oxidosqualene-cyclases) TwOSC1 and TwOSC3 cyclize to friedelin, the first committed step; friedelin is then converted through C-29 hydroxylation and carboxylation to polpunonic acid, followed by further oxidations and rearrangements to celastrol.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10038137/) Cytochrome P450 enzymes TwCYP712K1 and TwCYP712K2, characterized by in vivo yeast and in vitro enzyme assays, illuminate the second biosynthetic step.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10038137/) A 2023 *Nature Chemistry* study reported the elucidation of the 11 missing steps of the biosynthetic route, enabling de novo biosynthesis of celastrol in yeast.[17](https://www.nature.com/articles/s41557-023-01245-7) A biotechnological route combining yeast-based metabolic engineering with chemical synthesis has been established for scalable production from sucrose.[5](https://www.mdpi.com/1420-3049/31/20/3641)
**Total synthesis.** The first total synthesis of celastrol, and of any member of the celastroid family, was reported in 2015 by Andrew M. Camelio, Trevor C. Johnson, and Dionicio Siegel at the [University of Texas at Austin](https://www.edgepedia.org/university-of-texas-at-austin) and UC San Diego, starting from 2,3-dimethylbutadiene; a 12-step triene precursor underwent a ferric chloride-mediated polyene cyclization to build the pentacyclic core.[18](https://pubmed.ncbi.nlm.nih.gov/26331410/)
## Barriers to clinical translation
Celastrol's pharmacological promise is offset by severe physicochemical and toxicological constraints. Its water solubility is about 0.014 mg/mL (roughly 30 μM), it has low oral bioavailability and a short plasma half-life, and it shows dose-dependent cytotoxicity, hepatotoxicity, and organ toxicity.[9](https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1137289/full) • [10](https://pmc.ncbi.nlm.nih.gov/articles/PMC12420926/) In rat arthritis models, effective and non-toxic dosages fall between 2.5 and 5 mg/kg/day, with lower concentrations ineffective and higher concentrations showing signs of toxicity.[19](https://pmc.ncbi.nlm.nih.gov/articles/PMC9405053/) Despite decades of preclinical work, celastrol has not advanced to clinical trials for cancer in human subjects.[11](https://www.sciencedirect.com/science/article/pii/S0304383521004274)
**Delivery strategies.** Two broad approaches address these limits: direct chemical modification, including nucleic acid aptamer–celastrol conjugates, aptamer–dendrimer conjugates, and glucolipid conjugates; and indirect nanocarrier systems such as dendrimers, polymers, albumin carriers, liposomes, exosomes, and phytosomes.[9](https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1137289/full) A nucleic acid aptamer–celastrol conjugate raised apparent water solubility to at least 17.8 mg/mL and showed lower IC50 values against PANC-1 pancreatic cancer cells than free celastrol, with reduced liver accumulation.[9](https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1137289/full) Phytosomal nanocarriers improved oral bioavailability in rabbits, with a fourfold increase in AUC0-8 and a fivefold increase in Cmax.[9](https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1137289/full) Glycosylation by biotransformation has produced a derivative with over 53-fold higher water solubility and 50-fold less toxicity than celastrol in vivo.[20](https://pmc.ncbi.nlm.nih.gov/articles/PMC9013942/)
Clinical evidence remains sparse. A study involving 276 patients found that combining celastrol with oral nifedipine significantly reduced hypertension in pregnancy-induced preeclampsia without an increased incidence of severe maternal or neonatal adverse reactions, and a phase II/III trial of a celastrol solution in fracture patients has been registered, but safety and efficacy in humans have not been fully established.[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC12380071/)
## References
1. [Celastrol, CID 122724, PubChem](https://pubchem.ncbi.nlm.nih.gov/compound/Celastrol)
2. [Lu Y. et al. (2021). Biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of the quinone-methide triterpenoid celastrol. Medicinal Research Reviews.](https://pubmed.ncbi.nlm.nih.gov/33174200/)
3. [Construction, structural modification, and bioactivity evaluation of pentacyclic triterpenoid privileged scaffolds, RSC Advances (2024)](https://pubs.rsc.org/en/content/articlehtml/2024/ra/d4ra07602h)
4. [Pei T. et al. (2021). The genome of Tripterygium wilfordii and characterization of the celastrol biosynthesis pathway. Gigabyte.](https://pmc.ncbi.nlm.nih.gov/articles/PMC10038137/)
5. [Celastrol and Its Derivatives in Breast, Ovarian, and Cervical Cancer, Molecules (2025)](https://www.mdpi.com/1420-3049/31/20/3641)
6. [Zhang T. et al. (2009). Characterization of Celastrol to Inhibit Hsp90 and Cdc37 Interaction. Journal of Biological Chemistry.](https://pmc.ncbi.nlm.nih.gov/articles/PMC2790967/)
7. [Competitive profiling of celastrol targets in human cervical cancer HeLa cells via quantitative chemical proteomics, Molecular BioSystems (2017)](https://pubs.rsc.org/en/content/articlehtml/2017/mb/c6mb00691d)
8. [Liu J. et al. (2015). Treatment of obesity with celastrol. Cell 161, 999–1011.](https://pubmed.ncbi.nlm.nih.gov/26000480/)
9. [Recent advances in drug delivery of celastrol for enhancing efficiency and reducing the toxicity, Frontiers in Pharmacology (2024)](https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1137289/full)
10. [From Physicochemical Constraints to Clinical Prospects of Celastrol: Challenges and Nano Delivery Strategies, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC12420926/)
11. [Celastrol in cancer therapy: Recent developments, challenges and prospects, Cancer Letters (2021)](https://www.sciencedirect.com/science/article/pii/S0304383521004274)
12. [Emerging Target Discovery Strategies Drive the Decoding of Therapeutic Power of Natural Products: A Case Study of Celastrol, Exploration (2025)](https://pmc.ncbi.nlm.nih.gov/articles/PMC12380071/)
13. [Degradation-Based Protein Profiling: A Case Study of Celastrol, Advanced Science (2024)](https://pmc.ncbi.nlm.nih.gov/articles/PMC11220716/)
14. [Greenhill C. (2015). Celastrol identified as a leptin sensitizer and potential novel treatment for obesity. Nature Reviews Endocrinology 11, 444.](https://www.nature.com/articles/nrendo.2015.94)
15. [Feng X. et al. (2019). IL1R1 is required for celastrol's leptin-sensitization and antiobesity effects. Nature Medicine 25, 575–582.](https://www.nature.com/articles/s41591-019-0358-x)
16. [Celastrol Protects against Obesity and Metabolic Dysfunction through Activation of a HSF1-PGC1α Transcriptional Axis, Cell Metabolism (2015)](https://pubmed.ncbi.nlm.nih.gov/26344102/)
17. [Biosynthesis and biotechnological production of the anti-obesity agent celastrol, Nature Chemistry (2023)](https://www.nature.com/articles/s41557-023-01245-7)
18. [Camelio A.M., Johnson T.C., Siegel D. (2015). Total Synthesis of Celastrol, Development of a Platform to Access Celastroid Natural Products. J. Am. Chem. Soc. 137, 11864–11867.](https://pubmed.ncbi.nlm.nih.gov/26331410/)
19. [Celastrol: A Promising Agent Fighting against Cardiovascular Diseases, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9405053/)
20. [Celastrol: An Update on Its Hepatoprotective Properties and the Linked Molecular Mechanisms, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9013942/)
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*Topic: Encyclopedia › Physical world and mathematics › Chemistry › Organic substances › Carbonyl and carboxyl chemistry*
*Initially written Oct 15, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license