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

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.