Celastrol at the obesity-cancer interface: critical appraisal of molecular mechanisms, preclinical evidence, and translational barriers.

Authors

Asma B Omer, Muhammad Afzal, Shakir Saleem, Mohd Masih Uzzaman Khan, A Rekha, Rajat Sharma

Published in

Molecular biology reports. Volume 53. Issue 1. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

Obesity is a modifiable risk factor for various malignancies and is mechanistically linked to hyperinsulinemia, insulin-like growth factor 1 (IGF-1) activation, adipokine imbalance, mitochondrial oxidative stress, and chronic low-grade inflammation. Tripterygium wilfordii-derived celastrol is a quinone-methide triterpenoid that possesses multiple activities targeting metabolic, inflammatory, and oncogenic signaling networks. The molecular evidence of celastrol at the obesity-cancer interface is critically discussed, particularly focusing on metabolic reprogramming, adipokine signalling, inflammatory pathways, and the validity of the experimental models used. Celastrol increases leptin sensitivity in cell-based and animal studies, inhibits phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) signaling, disrupts heat shock protein 90-cell division cycle 37 (Hsp90-Cdc37) client-protein stabilization, and induces adenosine monophosphate-activated protein kinase (AMPK) activation, lipophagy, apoptosis, and autophagy. However, most of the antitumor effects observed are obtained from classic cancer cell lines or non-obese xenografts, and there is still limited direct evidence from diet-induced obesity models, adipocyte-tumor co-cultures, and obesity-associated models. The advantages of nanoformulations for solubility and tumor delivery in preclinical systems are significantly qualified by the lack of oral bioavailability, reactive metabolite hepatotoxicity, unclear dose-exposure relationships, narrow therapeutic window, and lack of human oncology trials. As such, at the present time, celastrol should be viewed as a preclinical molecular lead, but not a therapeutic candidate per se.

PMID:
42467316
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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