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Review
. 2024 Oct 7;20(14):5510-5530.
doi: 10.7150/ijbs.99592. eCollection 2024.

Recent Trends in anti-tumor mechanisms and molecular targets of celastrol

Yongping Zhu  1 , Yuqing Meng  1 , Junzhe Zhang  1 , Rui Liu  2 , Shengnan Shen  1 , Liwei Gu  1 , Yin-Kwan Wong  3 , Ang Ma  1 , Xin Chai  1 , Ying Zhang  1 , Yanqing Liu  1 , Jigang Wang  1   4   5
Affiliations
Review

Recent Trends in anti-tumor mechanisms and molecular targets of celastrol

Yongping Zhu et al. Int J Biol Sci. .

Abstract

Celastrol, a compound derived from traditional Chinese medicine, has therapeutic effects and has been used to treat inflammation-related diseases, cancer, cardiovascular diseases, and neurodegenerative diseases. However, current reviews lack a comprehensive and systematic summary of the anti-tumor mechanisms and molecular targets of celastrol. For this reason, this paper reviews the anticancer properties of celastrol and the molecular mechanisms underlying its anticancer effects. This paper primarily focuses on the mechanism of action of celastrol in terms of inhibition of cell proliferation and regulation of the cell cycle, regulation of apoptosis and autophagy, inhibition of cell invasion and metastasis, anti-inflammation, regulation of immunotherapy, and angiogenesis. More importantly, the target proteins of celastrol identified by chemical proteomics or other methods are highlighted, providing detailed targets with novel therapeutic potential for anti-tumor treatment. In addition, we describe the side effects and strategies to improve the bioavailability of celastrol. In summary, this paper analyzes celastrol, a natural compound with therapeutic effects and clear targets, aiming to draw more attention from the scientific and pharmacological communities and accelerating its clinical application for the benefit of cancer patients.

Keywords: celastrol; mechanisms; pharmacology; targets.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The molecular mechanisms of tumor suppression by celastrol. Celastrol attenuates tumor growth through various mechanisms, including inhibiting cell proliferation and regulating the cell cycle, regulating cell apoptosis and autophagy, inhibiting cell invasion and metastasis, anti-inflammatory properties, regulating tumor immunotherapy and angiogenesis.
Figure 2
Figure 2
Chemical structures of celastrol and its available probes.
Figure 3
Figure 3
Flow chart of chemical proteomics related to celastrol.
Figure 4
Figure 4
Direct binding targets of celastrol. (A) Celastrol covalently binds to the HSP90 co-chaperones Cdc37 and p23 to disrupt the Cdc37-HSP90 or p23-HSP90 complex. (B). Celastrol directly binds to Nedd4 and inhibits the interaction between Nedd4 and Nrf2, reducing the K48-linked ubiquitylation of Nrf2. (C). Celastrol directly binds and inhibits STAT3 tyrosine phosphorylation and nuclear translocation. (D). Celastrol targets Prdx1 to inhibit ROS production and suppress the proliferation of colorectal cancer cells. (E). Celastrol covalently binds to Nur77 and induces Nur77 interaction with TRAF2 to inhibit the classical IKK/NF-κB pathway.
Figure 5
Figure 5
Strategies to improve the bioavailability of celastrol. We summarize the methods used to ameliorate the shortcomings of low bioavailability, low water solubility and inadequate targeting of celastrol, including drug combination, nano-delivery and target identification.
Figure 6
Figure 6
The main toxicities of celastrol include hepatotoxicity, cardiotoxicity, infertility toxicity, hematopoietic system toxicity and nephrotoxicity.
See this image and copyright information in PMC

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