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Targeting metabolic diseases with celastrol: A comprehensive review of anti-inflammatory mechanisms and therapeutic potential

Wang X, Abu Bakar MH, Liqun S, Kassim MA, Shariff KA, Karunakaran T

J Ethnopharmacol, 2025 Mar 26;344:119560.
PMID: 40015541 DOI: 10.1016/j.jep.2025.119560

ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii is a traditional Chinese medicine used to treat rheumatic diseases, with properties such as clearing heat, detoxifying, dispelling wind, and relieving pain. In recent years, its active compound, celastrol, garnered significant attention for its potential therapeutic effects on metabolic diseases. Celastrol exhibits bioactivities such as regulating metabolic functions and anti-inflammatory effects, positioning it as a promising candidate for the treatment of obesity, diabetes, atherosclerosis (AS), and non-alcoholic fatty liver disease (NAFLD).
AIM OF THE REVIEW: This review aims to explore the pharmacological mechanisms of celastrol in metabolic diseases, focusing on its anti-inflammatory mechanisms and metabolic regulation effects, providing theoretical support for further investigation of its therapeutic potential in metabolic diseases.
METHODS: Literature was retrieved from PubMed, Web of Science, Scopus, Cochrane, and Google Scholar. This review primarily focuses on anti-inflammatory mechanisms of celastrol, its metabolic regulation, and toxicity studies, by systematically analyzing its effects in obesity, diabetes, AS, and NAFLD, providing scientific evidence for its potential clinical applications.
RESULTS: Celastrol regulates multiple signaling pathways, particularly inhibiting NF-κB and activating AMPK, reducing the production of pro-inflammatory cytokines and improving insulin sensitivity, enhancing its therapeutic potential in metabolic diseases. Additionally, celastrol regulates adipogenesis and energy metabolism by influencing key transcription factors such as PPARγ and SREBP-1c. Numerous studies highlight its role in alleviating oxidative stress and improving mitochondrial function, further enhancing its metabolic benefits.
CONCLUSION: In summary, celastrol holds great promise as a multi-target therapeutic agent for metabolic diseases, offering anti-inflammatory, metabolic regulatory, and antioxidative benefits. Despite these, challenges remain for the clinical application of celastrol due to its poor bioavailability and potential toxicity. Advanced formulation strategies and targeted delivery systems are urgently needed to overcome challenges related to bioavailability and clinical translation.

Matched MeSH terms: Tripterygium/chemistry
Fulltext Molecular modulators of celastrol as the keystones for its diverse pharmacological activities

Ng SW, Chan Y, Chellappan DK, Madheswaran T, Zeeshan F, Chan YL, et al.

Biomed Pharmacother, 2019 Jan;109:1785-1792.
PMID: 30551432 DOI: 10.1016/j.biopha.2018.11.051

In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such example that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future; along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.

Matched MeSH terms: Tripterygium*
Fulltext Triptolide inhibits epithelial-mesenchymal transition phenotype through the p70S6k/GSK3/β-catenin signaling pathway in taxol-resistant human lung adenocarcinoma

Tian Y, Li P, Xiao Z, Zhou J, Xue X, Jiang N, et al.

Transl Lung Cancer Res, 2021 Feb;10(2):1007-1019.
PMID: 33718039 DOI: 10.21037/tlcr-21-145

Background: Chemotherapy is one of the primary treatments for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), however, chemoresistance develops over time and is a bottleneck to effective chemotherapy worldwide. Therefore, the development of new potent therapeutic agents to overcome chemoresistance is of utmost importance. Triptolide is a natural component extracted from Tripterygium Wilfordii, a Chinese plant; our study aimed to evaluate its anti-tumor effects in taxol-resistant human lung adenocarcinoma and investigate its molecular mechanisms of chemoresistance.
Methods: Triptolide's inhibition of cell viability was detected by sulforhodamine B (SRB) assay. Cell cycle was measured by flow cytometry and cell apoptosis was assessed by flow cytometry and western blot. Expression of β-catenin was analyzed by western blot and immunofluorescence (IF). The anti-tumor effects of triptolide were determined using a subcutaneous in-vivo model. Cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, respectively. The expression level of p-p70S6K and p-GSK-3α/β was evaluated by western blot and IHC.
Results: Triptolide inhibited cell proliferation, induced S-phase cell cycle arrest and apoptosis in taxol-resistant A549 (A549/TaxR) cells. Moreover, intraperitoneal injection of triptolide resulted in a significant delay of tumor growth without obvious systemic toxicity in mice. Additionally, triptolide reversed epithelial-mesenchymal transition (EMT) through repression of the p70S6K/GSK3/β-catenin signaling pathway.
Conclusions: Our study provides evidence that triptolide can reverse EMT in taxol-resistant lung adenocarcinoma cells and impairs tumor growth by inhibiting the p70S6K/GSK3/β-catenin pathway, indicating that triptolide has potential to be used as a new therapeutic agent for taxol-resistant lung adenocarcinoma.

Matched MeSH terms: Tripterygium
Improvement of mitochondrial function by celastrol in palmitate-treated C2C12 myotubes via activation of PI3K-Akt signaling pathway

Abu Bakar MH, Tan JS

Biomed Pharmacother, 2017 Sep;93:903-912.
PMID: 28715871 DOI: 10.1016/j.biopha.2017.07.021

Compelling evidences posited that high level of saturated fatty acid gives rise to mitochondrial dysfunction and inflammation in the development of insulin resistance in skeletal muscle. Celastrol is a pentacyclic triterpenoid derived from the root extracts of Tripterygium wilfordii that possesses potent anti-inflammatory properties in a number of animal models with metabolic diseases. However, the cellular mechanistic action of celastrol in alleviating obesity-induced insulin resistance in skeletal muscle remains largely unknown. Therefore, the present investigation evaluated the attributive properties of celastrol at different concentrations (10, 20, 30 and 40nM) on insulin resistance in C2C12 myotubes evoked by palmitate. We demonstrated that celastrol improved mitochondrial functions through significant enhancement of intracellular ATP content, mitochondrial membrane potential, citrate synthase activity and decrease of mitochondrial superoxide productions. Meanwhile, augmented mitochondrial DNA (mtDNA) content with suppressed DNA oxidative damage were observed following celastrol treatment. Celastrol significantly enhanced fatty acid oxidation rate and increased the level of tricarboxylic acid (TCA) cycle intermediates in palmitate-treated cells. Further analysis revealed that the improvement of glucose uptake activity in palmitate-loaded myotubes was partly mediated by celastrol via activation of PI3K-Akt insulin signaling pathway. Collectively, these findings provided evidence for the first time that the protection from palmitate-mediated insulin resistance in C2C12 myotubes by celastrol is likely associated with the improvement of mitochondrial functions-related metabolic activities.

Matched MeSH terms: Tripterygium