2. Academic Validation
  3. WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis

WGX50 mitigates doxorubicin-induced cardiotoxicity through inhibition of mitochondrial ROS and ferroptosis

  • J Transl Med. 2023 Nov 17;21(1):823. doi: 10.1186/s12967-023-04715-1.
Panpan Tai # 1,  Xinyu Chen # 1,  Guihua Jia 2,  Guanjun Chen 1,  Lian Gong 1,  Yaxin Cheng 1,  Zhuan Li 3 4 5,  Heng Wang 2,  Aiyan Chen 1,  Ganghua Zhang 1,  Yuxing Zhu 1,  Mengqing Xiao 1,  Zhanwang Wang 1,  Yunqing Liu 1,  Dongyong Shan 1,  Dong He 6,  Moying Li 7,  Tianzuo Zhan 7,  Abbas Khan 2,  Xiaohui Li 8,  Xiangxiang Zeng 9,  Chaopeng Li 10,  Dongsheng Ouyang 10 11,  Kelong Ai 12 13,  Xuan Chen 14 15 16,  Dongbo Liu 14 15 16,  Zhonghua Liu 16,  Dongqing Wei 17,  Ke Cao 18
Affiliations

Affiliations

  • 1 Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China.
  • 2 School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 3 The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Hunan Normal University School of Medicine, Changsha, 410013, China.
  • 4 The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University School of Medicine, Changsha, 410013, China.
  • 5 Department of Pharmacy, Hunan Normal University School of Medicine, Changsha, 410013, China.
  • 6 Staff Hospital of Central South University, Central South University, Changsha, China.
  • 7 Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • 8 Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
  • 9 College of Computer Science and Electronic Engineering, Hunan University, Changsha, China.
  • 10 Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd, Changsha, China.
  • 11 Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
  • 12 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
  • 13 Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
  • 14 College of Horticulture, Hunan Agricultural University, Changsha, China.
  • 15 State Key Laboratory of Subhealth Intervention Technology, Changsha, China.
  • 16 National Research Center of Engineering Technology for Utilization Ingredients From Botanicals, Changsha, China.
  • 17 School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. dqwei@sjtu.edu.cn.
  • 18 Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, China. csucaoke@163.com.
  • # Contributed equally.
PMID: 37978379 DOI: 10.1186/s12967-023-04715-1
Abstract

Background: Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear.

Methods: We established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and Ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes.

Results: Our findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and Ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced Ferroptosis.

Conclusion: Taken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the Ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.

Keywords

DOX-induced cardiotoxicity; Ferroptosis; GPX4; Mitochondrial ROS; WGX50.

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