Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma

• Published in: Asian journal of pharmceutical sciences Vol. 18; no. 6; pp. 100874 - 174
• Main Authors: Luo, Piao, Zhang, Qian, Shen, Shuo, An, Yehai, Yuan, Lixia, Wong, Yin-Kwan, Huang, Sizhe, Huang, Shaohui, Huang, Jingnan, Cheng, Guangqing, Tian, Jiahang, Chen, Yu, Zhang, Xiaoyong, Li, Weiguang, He, Songqi, Wang, Jigang, Du, Qingfeng
• Format: Journal Article
• Language: English
• Published: Netherlands Department of Oncology,the Affiliated Hospital of Southwest Medical University,Luzhou 646000,China 01.11.2023; Department of Biological Sciences,National University of Singapore,Singapore 117543,Singapore; 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; School of Traditional Chinese Medicine and School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China%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%Department of Biological Sciences,National University of Singapore,Singapore 117543,Singapore%Department of Nephrology,Shenzhen key Laboratory of Kidney Diseases,and Shenzhen Clinical Research Centre for Geriatrics,Shenzhen People's Hospital,The First Affiliated Hospital,Southern University of Science and Technology,Shenzhen 518020,China%Department of Health Technology and Informatics,The Hong Kong Polytechnic University,Hong Kong 100872,China%School of Traditional Chinese Medicine and School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China; National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine,Jiangxi University of Chinese Medicine,Nanchang 330006,China; Shenyang Pharmaceutical University; Elsevier
• Subjects: Apoptosis; Celastrol; Ferroptosis; Hepatocellular carcinoma; Liposomes; VDAC2; Ferroptosis; Hepatocellular carcinoma; VDAC2; Liposomes; Celastrol; Apoptosis
• ISSN: 1818-0876; 2221-285X; 2221-285X
• DOI: 10.1016/j.ajps.2023.100874

Hepatocellular carcinoma (HCC) is one of most common and deadliest malignancies. Celastrol (Cel), a natural product derived from the plant, has been extensively researched for its potential effectiveness in fighting cancer. However, its clinical application has been hindered by the unclear mechanism of action. Here, we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and anti-tumor capacity by developing a Cel-based liposomes in HCC. We demonstrated that Cel selectively targets the voltage-dependent anion channel 2 (VDAC2). Cel directly binds to the cysteine residues of VDAC2, and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore (mPTP) function. We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells. Moreover, coencapsulation of Cel into alkyl glucoside-modified liposomes (AGCL) improved its antitumor efficacy and minimized its side effects. AGCL has been shown to effectively suppress the proliferation of tumor cells. In a xenograft nude mice experiment, AGCL significantly inhibited tumor growth and promoted apoptosis. Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death, while the Cel liposomes enhance its targetability and reduces side effects. Overall, Cel shows promise as a therapeutic agent for HCC.