Single-cell profiling reveals immunoregulation of artemisinin on CD8+GZMB+ T cells via JAK2-STAT3 in malaria-infected mice

Jiayun Chen; Peng Gao; Xueling He; Yanwei Hu; Wei Zhou; Yanxia Liu; Jianyou Wang; Xiaohong Liu; Yunmeng Bai; Lina Chen; Chen Wang; Guangqing Cheng; Xing Zhang; Yin Kwan Wong; Fulong Liao; Chengchao Xu; Juanjuan Ou; Yiqiang Wu; Wei Zhang; Yue Gao; Youyou Tu; Jigang Wang

doi:10.1016/j.xinn.2025.101080

Single-cell profiling reveals immunoregulation of artemisinin on CD8⁺GZMB⁺ T cells via JAK2-STAT3 in malaria-infected mice

Innovation (Camb). 2025 Aug 14;6(9):101080. doi: 10.1016/j.xinn.2025.101080. eCollection 2025 Sep 8.

Authors

Jiayun Chen^{1

2

3

4}, Peng Gao^{1

2}, Xueling He^{1

2}, Yanwei Hu⁵, Wei Zhou⁶, Yanxia Liu^{1

2}, Jianyou Wang^{1

2}, Xiaohong Liu^{7

8}, Yunmeng Bai³, Lina Chen^{1

2}, Chen Wang^{1

2}, Guangqing Cheng^{1

2}, Xing Zhang^{1

2}, Yin Kwan Wong⁹, Fulong Liao^{1

2}, Chengchao Xu^{1

2}, Juanjuan Ou¹⁰, Yiqiang Wu¹¹, Wei Zhang^{7

12}, Yue Gao⁶, Youyou Tu^{1

2}, Jigang Wang^{1

2

3

4}

Affiliations

¹ State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, China Academy of Chinese Medical Sciences, Beijing 100700, China.
² Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
³ Department of Critical Care Medicine, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518020, China.
⁴ Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou Guangdong 510006, China.
⁵ Department of Laboratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
⁶ Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China.
⁷ Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China.
⁸ National University of Singapore (Chongqing) Research Institute, Chongqing 401123, China.
⁹ Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117543, Singapore.
¹⁰ Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, University of Electronic Science and Technology of China, Chengdu 610042, China.
¹¹ State Key Laboratory of Woody Oil Resources Utilization, Central South University of Forestry and Technology, Changsha 410004, China.
¹² School of Chemical Engineering, Xinjiang University, Urumqi 830017, China.

Abstract

Malaria, a pervasive and devastating disease, is characterized by systemic complications and dysregulated host immune responses to Plasmodium infection. Artemisinin derivatives, particularly artesunate (ART), are a cornerstone in malaria treatment strategies. Although the precise immunomodulatory mechanisms remain unclear, ART not only kills parasites but also impacts host immune homeostasis. In this study, we employed single-cell RNA sequencing to characterize the cellular landscape of 241,837 cells from multiple murine tissues (including liver, spleen, and peripheral blood) upon Plasmodium berghei ANKA (PbA) infection and after ART treatment. Meanwhile, we observed significant transcriptomic shifts across diverse immune cell types, with the liver exhibiting the most pronounced changes in response to PbA infection. Notably, CD8⁺GZMB⁺ T lymphocytes, characterized by elevated cytokine and cytotoxic module scores, play a pivotal role in driving hepatic injury. Furthermore, ART modulated this pathogenic subtype via the JAK2-STAT3 pathway, reducing its frequency and mitigating its inflammatory response. Our research provides a valuable dataset resource for exploring malaria immunopathogenesis and elucidates a novel immunoregulatory mechanism of ART within the infected host.

Keywords: CD8+GZMB+ T lymphocyte; artemisinin; immunoregulation; malaria; multiple tissues; single-cell RNA sequencing.