Celastrol inhibits the DPYSL2-JAK/STAT pathway by targeting mito-IDHs mediated mitochondrial metabolism to exhaust breast cancer
Qiao-li Shi1,
Chen-ran Feng1,
Hui-ying Li2,3,
Pei-li Wang4,
Peng Chen5,
Xu Wei6,
Wen-hua Kuang2,
Guan-jun Li2,
Shi-jie Qin7,
Rui Liu1,
Rui-xing Chen1,
Jun-zhe Zhang1,
Ping Song4,
Yuan Yuan5,
Ji-gang Wang1,2,3,8,
Ling Huang1,2
1 State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
2 Department of Critical Care Medicine, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, China
3 Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Dongguan 523000, China
4 National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100700, China
5 Experimental Research Center, China Academy of Traditional Chinese Medicine, Beijing 100700, China
6 Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100700, China
7 Innovative Vaccine and Immunotherapy Research Center, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310009, China
8 State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng 475004, China
Correspondence to: Ping Song: songping@vip.126.com, Yuan Yuan: y_yuan0732@163.com, Ji-gang Wang: jgwang@icmm.ac.cn, Ling Huang: huangl2024@mail.sustech.edu.cn,
DOI: 10.1038/s41401-025-01548-0
Received: 25 September 2024
Accepted: 18 March 2025
Advance online: 24 April 2025
Abstract
Targeting mitochondrial metabolism represents a novel approach in the discovery and development of anti-tumor drugs. Celastrol (Cel) is a naturally-derived small molecule from Tripterygium wilfordii with significant anticancer activities. In this study, we investigated the anti-tumor mechanisms involving mitochondrial metabolic reprogramming regulated by Cel in breast cancer (BRCA). We showed that Cel potently inhibited the proliferation of triple-negative breast cancer cells (MDA-MB-231) and ER+ breast cancer cells (MCF-7) with IC50 values of 2.15 μM and 2.29 μM, respectively. Administration of Cel (5, 2, 2 mg/kg, i.p. for three times after tumor formation) significantly suppressed the tumor growth in syngeneic allograft and CDX breast cancer mouse models. Using activity-based protein profiling (ABPP) technology, we identified mitochondrial isocitrate dehydrogenases (including IDH2 and IDH3A, collectively referred to as mito-IDHs) as direct targets of Cel. We demonstrated that Cel significantly inhibited mito-IDHs mediated mitochondrial metabolism to induce the accumulation of metabolites α-ketoglutaric acid, and that Cel enhanced the interaction between DPYSL2 with IDH3A while promoting the accumulation of DPYSL2 within mitochondria of BRCA cells resulting in inactivation of JAK/STAT pathway and ultimately induced ferroptosis and apoptosis in cancer cells. Collectively, this study elucidates a pharmacological mechanism by which Cel exerts its tumor-inhibiting effects through modulation of mitochondrial metabolism. Furthermore, it provides compelling evidence supporting Cel as a promising candidate for development as a small-molecule inhibitor targeting mitochondrial metabolism.
