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<p>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. <i>Tripterygium wilfordii-</i>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年7月17日

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

摘要

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.