Artesunate induces ferroptosis by regulating MT1G and has an additive effect with doxorubicin in diffuse large B-cell lymphoma cells

Dan Xiong; Chengjie Geng; Liyi Zeng; Hua Yao; Jiewen Tan; Lan Zhang; Xiaohui Liu; Langxia Liu

doi:10.1016/j.heliyon.2024.e28584

Artesunate induces ferroptosis by regulating MT1G and has an additive effect with doxorubicin in diffuse large B-cell lymphoma cells

Heliyon. 2024 Mar 22;10(7):e28584. doi: 10.1016/j.heliyon.2024.e28584. eCollection 2024 Apr 15.

Authors

Dan Xiong¹, Chengjie Geng², Liyi Zeng², Hua Yao², Jiewen Tan¹, Lan Zhang², Xiaohui Liu², Langxia Liu²

Affiliations

¹ Department of Hematology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong, 528308, China.
² MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou, 510632, China.

Abstract

Diffuse Large B-cell lymphoma (DLBCL) is a highly aggressive disease with heterogeneous outcomes and marked variability in the response to chemotherapy. DLBCL comprises two major subtypes: germinal centre B-cell-like (GCB) and activated B-cell-like (ABC). Our study highlights the extensive antitumour activity of artesunate (ART) against both major DLBCL subtypes. Transcriptome analysis suggests the potential involvement of ferroptosis in artesunate-induced cell death. Because of low glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels, along with the accumulation of free iron (Fe²⁺), artesunate induces the excessive production of reactive oxygen species (ROS), ultimately leading to ferroptosis, a form of cell death driven by phospholipid peroxidation. A putative target of artesunate, metallothionein 1G (MT1G), was selected for further analysis. Subsequent studies revealed that inhibiting MT1G expression in vitro significantly impedes the ferroptosis-promoting activity of artesunate by reducing lipid peroxidation and iron accumulation. We also showed that the combination of artesunate and doxorubicin had a marked additive inhibitory effect on GCB and ABC DLBCL cells. In conclusion, artesunate induces ferroptotic death in GCB and ABC DLBCL cells by attenuating the GPX4/GSH antioxidant defence system and increasing intracellular iron levels, indicating its therapeutic potential for relapsed or refractory DLBCL.