Mechanistic insights into the renoprotective effects of artesunate in cisplatin-induced acute kidney injury

Hetao Chen; Ran Guo; Chenning Zhang; Lei Zhang; Hongxia Hu; Peipei Du; Jiajia Duan; Lulu Chen; Xiao Ma; Juan Xue; Yanwen Mao; Tao Jiang

doi:10.1016/j.lfs.2025.123820

Mechanistic insights into the renoprotective effects of artesunate in cisplatin-induced acute kidney injury

Life Sci. 2025 Jun 25:123820. doi: 10.1016/j.lfs.2025.123820. Online ahead of print.

Authors

Hetao Chen¹, Ran Guo¹, Chenning Zhang², Lei Zhang³, Hongxia Hu¹, Peipei Du¹, Jiajia Duan¹, Lulu Chen¹, Xiao Ma¹, Juan Xue¹, Yanwen Mao⁴, Tao Jiang⁵

Affiliations

¹ Department of Clinical Laboratory, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China.
² Department of Pharmacy, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang 441000, China.
³ Department of Integrative Medicine, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China.
⁴ Academy of Medical, Henan University of Chinese Medicine, Zhengzhou 450018, China. Electronic address: maoyanwen@hactcm.edu.cn.
⁵ Department of Clinical Laboratory, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China. Electronic address: jyk01@stu.haust.edu.cn.

PMID: 40578675
DOI: 10.1016/j.lfs.2025.123820

Abstract

Acute kidney injury (AKI) is a severe clinical syndrome marked by rapid renal function decline. Cisplatin (Cis) is a commonly used chemotherapy agent; however, its clinical application has been restricted due to its nephrotoxicity. Artesunate (ART), derived from Artemisia annua, has potent anti-inflammatory and antioxidant properties. However, its potential to mitigate cisplatin-induced AKI has yet to be fully investigated. This study investigates ART's protective effects against cisplatin-induced AKI and explores its molecular mechanisms. In vivo experiments on C57BL/6 mice were divided into control, cisplatin, and cisplatin + ART groups with different doses. Kidney tissues were analyzed histologically and molecularly. In vitro, HK-2 cells were used to assess cell viability, apoptosis, oxidative stress, and ferroptosis. Network pharmacology and molecular docking predicted ART's targets and interactions. Results demonstrated that ART significantly reduced serum creatinine (Scr) and blood urea nitrogen (BUN) levels, while concurrently improving renal histopathological features. In vitro, ART enhanced cell viability, reduced apoptosis, and decreased reactive oxygen species (ROS). ART increased glutathione (GSH) levels and reduced malondialdehyde (MDA) and Fe²⁺ levels. ART restored mitochondrial membrane potential and ultrastructure in cisplatin-treated cells and upregulated key proteins in the ferroptosis pathway, including GSK3β, PARP1, SLC7A11, and GPX4. Molecular docking studies predict that ART interacts with GSK3β and PARP1. ART significantly alleviates cisplatin-induced acute kidney injury by inhibiting ferroptosis through the GSK3β/PARP1/SLC7A11 signaling pathway. This study provides strong evidence for the therapeutic potential of ART in AKI and highlights the need for further research into its molecular mechanisms and clinical applications.

Keywords: Acute kidney injury; Artesunate; Ferroptosis; GSK3β/PARP1/SLC7A11 signaling pathway.