Celastrol
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{{chembox
| ImageFile = Celastrol.svg
| ImageSize = 200px
| IUPACName = 3-Hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic acid
| SystematicName = (2R,4aS,6aS,12bR,14aS,14bR)-10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydropicene-2-carboxylic acid
| OtherNames = Tripterine
|Section1={{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 34157-83-0
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = L8GG98663L
| ChEMBL_Ref =
| PubChem = 122724
| ChemSpiderID = 109405
| SMILES = CC1=C(C(=O)C=C2C1=CC=C3[C@]2(CC[C@@]4([C@@]3(CC[C@@]5([C@H]4C[C@](CC5)(C)C(=O)O)C)C)C)C)O
| InChI = 1/C29H38O4/c1-17-18-7-8-21-27(4,19(18)15-20(30)23(17)31)12-14-29(6)22-16-26(3,24(32)33)10-9-25(22,2)11-13-28(21,29)5/h7-8,15,22,31H,9-14,16H2,1-6H3,(H,32,33)/t22-,25-,26-,27+,28-,29+/m1/s1
| InChIKey = KQJSQWZMSAGSHN-JJWQIEBTBS
| StdInChI = 1S/C29H38O4/c1-17-18-7-8-21-27(4,19(18)15-20(30)23(17)31)12-14-29(6)22-16-26(3,24(32)33)10-9-25(22,2)11-13-28(21,29)5/h7-8,15,22,31H,9-14,16H2,1-6H3,(H,32,33)/t22-,25-,26-,27+,28-,29+/m1/s1
| StdInChIKey = KQJSQWZMSAGSHN-JJWQIEBTSA-N}}
|Section2={{Chembox Properties
| C=29 | H=38 | O=4
| Appearance =Crystalline solid
| Density =
| MeltingPtC = 213
| BoilingPt =
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|Section7={{Chembox Hazards
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Celastrol (tripterine) is a bioactive chemical compound isolated from the roots of Tripterygium wilfordii (Thunder duke vine) and Tripterygium regelii (Regel's threewingnut). Celastrol is a pentacyclic {{chem name|nortriterpen quinone}} and belongs to the family of quinone methides.{{cite journal | vauthors = Tan JL, Yi J, Cao XY, Wang FY, Xie SL, Zhou LL, Qin L, Dai AG | title = Celastrol: The new dawn in the treatment of vascular remodeling diseases | journal = Biomedicine & Pharmacotherapy | volume = 158 | pages = 114177 | date = February 2023 | pmid = 36809293 | doi = 10.1016/j.biopha.2022.114177 | doi-access = free }} It has been used for centuries as a traditional Chinese medicine. In recent years, celastrol has been widely studied for its anti-inflammatory, anticancer, antioxidant, and antibacterial properties.{{cite journal | vauthors = Lei H, Ruan Y, Ding R, Li H, Zhang X, Ji X, Wang Q, Lv S | title = The role of celastrol in inflammation and diseases | journal = Inflammation Research | volume = 74 | issue = 1 | pages = 23 | date = January 2025 | pmid = 39862265 | doi = 10.1007/s00011-024-01983-5 }}{{cite journal | vauthors = Kashyap D, Sharma A, Tuli HS, Sak K, Mukherjee T, Bishayee A | title = Molecular targets of celastrol in cancer: Recent trends and advancements | journal = Critical Reviews in Oncology/Hematology | volume = 128 | pages = 70–81 | date = August 2018 | pmid = 29958633 | doi = 10.1016/j.critrevonc.2018.05.019 }}{{cite journal | vauthors = Xu H, Zhao H, Ding C, Jiang D, Zhao Z, Li Y, Ding X, Gao J, Zhou H, Luo C, Chen G, Zhang A, Xu Y, Zhang H | title = Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1 | journal = Signal Transduction and Targeted Therapy | volume = 8 | issue = 1 | pages = 51 | date = February 2023 | pmid = 36732502 | pmc = 9895061 | doi = 10.1038/s41392-022-01231-4 }}{{cite journal | vauthors = Yuan Z, Wang J, Qu Q, Zhu Z, Xu M, Zhao M, Sun C, Peng H, Huang X, Dong Y, Dong C, Zheng Y, Yuan S, Li Y | title = Celastrol Combats Methicillin-Resistant Staphylococcus aureus by Targeting Δ1 -Pyrroline-5-Carboxylate Dehydrogenase | journal = Advanced Science | volume = 10 | issue = 25 | pages = e2302459 | date = September 2023 | pmid = 37381655 | pmc = 10477891 | doi = 10.1002/advs.202302459 }}
In mice, celastrol is an NR4A1 agonist that alleviates inflammation and induces autophagy.{{cite journal |vauthors=Zhang L, Wang Q, Liu W, Liu F, Ji A, Li Y |title=The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases |journal= Journal of Diabetes Research|volume=2018 |issue= |pages=9363461 |date=2018 |pmid=30013988 |pmc=6022324 |doi=10.1155/2018/9363461 |url= |doi-access=free}} It also influences metabolic regulation by enhancing IL1R1 expression, which is the receptor for the cytokine interleukin-1 (IL-1). IL1R1 knock-out mice exposed to celastrol exhibit no leptin-sensitizing or anti-obesity effect.{{cite journal |vauthors=Feng X, Guan D, Auen T, Choi JW, Salazar Hernández MA, Lee J, Chun H, Faruk F, Kaplun E, Herbert Z, Copps KD, Ozcan U |title=IL1R1 is required for celastrol's leptin-sensitization and antiobesity effects |journal=Nature Medicine |volume=25 |issue=4 |pages=575–582 |date=April 2019 |pmid=30833749 |doi=10.1038/s41591-019-0358-x |pmc=7158951}}
In in vitro and in vivo animal experiments, celastrol exhibits antibacterial,{{cite journal |vauthors=Padilla-Montaño N, de León Guerra L, Moujir L |title=Antimicrobial Activity and Mode of Action of Celastrol, a Nortriterpen Quinone Isolated from Natural Sources |journal=Foods |volume=10 |issue=3 |date=March 2021 |page=591 |pmid=33799720 |pmc=7998816 |doi=10.3390/foods10030591 |url=|doi-access=free }} antioxidant,{{cite journal | vauthors = Allison AC, Cacabelos R, Lombardi VR, Alvarez XA, Vigo C | title = Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 25 | issue = 7 | pages = 1341–57 | date = October 2001 | pmid = 11513350 | doi = 10.1016/S0278-5846(01)00192-0 | s2cid = 21569585 }} anti-inflammatory,{{cite journal | vauthors = Kim DH, Shin EK, Kim YH, Lee BW, Jun JG, Park JH, Kim JK | title = Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regelii | journal = European Journal of Clinical Investigation | volume = 39 | issue = 9 | pages = 819–27 | date = September 2009 | pmid = 19549173 | doi = 10.1111/j.1365-2362.2009.02186.x | s2cid = 205291261 }}{{cite journal | vauthors = Venkatesha SH, Yu H, Rajaiah R, Tong L, Moudgil KD | title = Celastrus-derived celastrol suppresses autoimmune arthritis by modulating antigen-induced cellular and humoral effector responses | journal = The Journal of Biological Chemistry | volume = 286 | issue = 17 | pages = 15138–46 | date = April 2011 | pmid = 21402700 | pmc = 3083183 | doi = 10.1074/jbc.M111.226365 | doi-access = free }} anticancer,{{cite journal | vauthors = Metselaar DS, Meel MH, Benedict B, Waranecki P, Koster J, Kaspers GJ, Hulleman E | title = Celastrol-induced degradation of FANCD2 sensitizes pediatric high-grade gliomas to the DNA-crosslinking agent carboplatin | journal = eBioMedicine | volume = 50 | pages = 81–92 | date = November 2019 | pmid = 31735550 | pmc = 6921187| doi = 10.1016/j.ebiom.2019.10.062 | doi-access = free }}{{cite journal | vauthors = Lee JH, Choi KJ, Seo WD, Jang SY, Kim M, Lee BW, Kim JY, Kang S, Park KH, Lee YS, Bae S | title = Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90 | journal = International Journal of Molecular Medicine | volume = 27 | issue = 3 | pages = 441–6 | date = March 2011 | pmid = 21249311 | doi = 10.3892/ijmm.2011.601 | doi-access = free }}{{cite journal | vauthors = Tiedemann RE, Schmidt J, Keats JJ, Shi CX, Zhu YX, Palmer SE, Mao X, Schimmer AD, Stewart AK | title = Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kappaB with antimyeloma activity in vitro and in vivo | journal = Blood | volume = 113 | issue = 17 | pages = 4027–37 | date = April 2009 | pmid = 19096011 | pmc = 3952546 | doi = 10.1182/blood-2008-09-179796 }}{{cite journal | vauthors = Zhu H, Liu XW, Cai TY, Cao J, Tu CX, Lu W, He QJ, Yang B | title = Celastrol acts as a potent antimetastatic agent targeting beta1 integrin and inhibiting cell-extracellular matrix adhesion, in part via the p38 mitogen-activated protein kinase pathway | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 334 | issue = 2 | pages = 489–99 | date = August 2010 | pmid = 20472666 | doi = 10.1124/jpet.110.165654 | s2cid = 25854329 }}{{cite journal | vauthors = Byun JY, Kim MJ, Eum DY, Yoon CH, Seo WD, Park KH, Hyun JW, Lee YS, Lee JS, Yoon MY, Lee SJ | title = Reactive oxygen species-dependent activation of Bax and poly(ADP-ribose) polymerase-1 is required for mitochondrial cell death induced by triterpenoid pristimerin in human cervical cancer cells | journal = Molecular Pharmacology | volume = 76 | issue = 4 | pages = 734–44 | date = October 2009 | pmid = 19574249 | doi = 10.1124/mol.109.056259 | s2cid = 6541041 }} and insecticidal properties.{{cite journal | vauthors = Avilla J, Teixidò A, Velázquez C, Alvarenga N, Ferro E, Canela R | title = Insecticidal activity of Maytenus species (Celastraceae) nortriterpene quinone methides against codling moth, Cydia pomonella (L.) (Lepidoptera: tortricidae) | journal = Journal of Agricultural and Food Chemistry | volume = 48 | issue = 1 | pages = 88–92 | date = January 2000 | pmid = 10637057 | doi = 10.1021/jf990008w | bibcode = 2000JAFC...48...88A }} It has been shown to have obesity-controlling effects in mice by inhibiting negative regulators of leptin.Kyriakou E, Schmidt S, Dodd GT, et al. Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus. J Med Chem. 2018;61(24):11144-11157. doi:10.1021/acs.jmedchem.8b01224{{cite journal | vauthors = Pfuhlmann K, Schriever SC, Baumann P, Kabra DG, Harrison L, Mazibuko-Mbeje SE, Contreras RE, Kyriakou E, Simonds SE, Tiganis T, Cowley MA, Woods SC, Jastroch M, Clemmensen C, De Angelis M, Schramm KW, Sattler M, Messias AC, Tschöp MH, Pfluger PT | title = Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1 | journal = Diabetes | volume = 67 | issue = 11 | pages = 2456–2465 | date = November 2018 | pmid = 30158241 | doi = 10.2337/db18-0146 | doi-access = free }}{{cite journal | vauthors = Liu J, Lee J, Salazar Hernandez MA, Mazitschek R, Ozcan U | title = Treatment of obesity with celastrol | journal = Cell | volume = 161 | issue = 5 | pages = 999–1011 | date = May 2015 | pmid = 26000480 | pmc = 4768733 | doi = 10.1016/j.cell.2015.05.011 }} Celastrol has also shown to possess anti-diabetic effects on diabetic nephropathy and improve whole-body insulin resistance, through the inhibition of NF-κB signaling in the hypothalamus.{{cite journal | vauthors = Kim JE, Lee MH, Nam DH, Song HK, Kang YS, Lee JE, Kim HW, Cha JJ, Hyun YY, Han SY, Han KH, Han JY, Cha DR | title = Celastrol, an NF-κB inhibitor, improves insulin resistance and attenuates renal injury in db/db mice | journal = PLOS ONE | volume = 8 | issue = 4 | pages = e62068 | year = 2013 | pmid = 23637966 | pmc = 3637455 | doi = 10.1371/journal.pone.0062068 | bibcode = 2013PLoSO...862068K | doi-access = free }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}
Celastrol inhibits the IKK-NF-κB signaling pathway via multiple molecular mechanisms, including the direct inhibition of IKKα and IKKβ kinases, inactivation of CDC37 and p23 (HSP90 chaperone proteins), suppression of proteasome function and activation of HSF1, which triggers the heat shock response. The available evidence indicates that celastrol covalently binds to the thiol groups of cysteine residues within its molecular targets.{{cite journal |vauthors=Salminen A, Lehtonen M, Paimela T, Kaarniranta K |title=Celastrol: Molecular targets of Thunder God Vine |journal=Biochem Biophys Res Commun |volume=394 |issue=3 |pages=439–42 |date=April 2010 |pmid=20226165 |doi=10.1016/j.bbrc.2010.03.050 |url=}}
Celastrol also has demonstrated in vitro inhibitory effects against the carbapenemase of carbapenem-resistant Klebsiella pneumoniae (CRE), particularly when used in combination with thymol, a monoterpene.{{cite journal|title=In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates|vauthors=Abdel-Halim MS, Askoura M, Mansour B, Yahya G, El-Ganiny AM|journal=The Journal of Antibiotics|date=27 September 2022|volume=75|issue=12 |pages=679–690|doi=10.1038/s41429-022-00566-y|doi-access=free|pmid=36167781 |pmc=9640353}}
Antibacterial activity against MRSA
Recent studies have identified celastrol as a potential antibacterial agent against methicillin-resistant Staphylococcus aureus (MRSA). Multi-omics analysis suggests that celastrol targets bacterial Δ¹-pyrroline-5-carboxylate dehydrogenase (P5CDH), which is an enzyme involved in proline metabolism. Molecular docking identified Lys205 and Glu208 as critical binding sites for celastrol on P5CDH.
By binding to P5CDH, celastrol disrupts its function and leads to an accumulation of Δ1-pyrroline-5-carboxylate (P5C). This disruption interferes with bacterial oxidative stress regulation, resulting in an increase in reactive oxygen species (ROS) and oxidative damage. Additionally, the inhibition of P5CDH disrupts bacterial energy production and DNA synthesis, ultimately leading to bacterial cell death. Because celastrol affects multiple bacterial metabolic pathways, it is a promising candidate for drug development.
Experiments in vitro demonstrated that celastrol exhibits significant antibacterial activity against Gram-positive bacteria, including multiple MRSA strains. However, it is significantly less effective against Gram-negative bacteria due to structural differences in their cell wall structures. The compound also demonstrated low levels of resistance development compared to traditional antibiotics such as vancomycin and oxacillin.
In vivo studies using Galleria mellonella larvae and murine infection models showed that celastrol effectively reduced bacterial burden and improved survival rates in MRSA-infected animals. However, high doses of celastrol led to toxicity, including hepatotoxicity and renal damage. Additionally, celastrol's therapeutic window is narrow, meaning that only a specific dosage range is effective. It was also shown that in high concentrations, celastrol induces apoptosis in spleen cells. These findings suggest that celastrol may not be suitable for direct clinical use. On the other hand, celastrol should be used as a lead compound for developing safer and more effective derivatives.