The Interaction Between Ferroptosis and Necroptosis in Acute and Chronic Kidney Diseases

Chenwen Song,1,2,* Fei Chen,1,2,* Yi Fang,3,* Xiaonan Ding,1,2,* Qiuxia Han,4 Yingjie Duan,1,2 Qinqin Ren,1,2 Dong Zhang,1,2 Hanyu Zhu1,2 1Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing, 100853, People’s Republic of China; 2Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine. (No: ZYYCXTD-D-202402), Beijing, 100853, People’s Republic of China; 3College of Medical, Nankai University, Tianjin, 300071, People’s Republic of China; 4Department of Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hanyu Zhu; Dong Zhang, Email [email protected]; [email protected]: Kidney disease represents a major non-communicable disease characterized by complex pathogenesis and limited therapeutic options. Current research has revealed multiple underlying mechanisms, including ferroptosis and necroptosis, which play important roles in acute kidney injury (AKI) and chronic kidney disease (CKD). Ferroptosis is an iron-dependent form of programmed cell death caused by the accumulation of lipid reactive oxygen species and is characterized by iron ion aggregation, lipid peroxidation, and excessive oxidative stress. Necroptosis is a regulated form of necrosis mediated by RIPK1–RIPK3 and is characterized by the recruitment and phosphorylation of the pseudokinase mixed lineage kinase domain-like protein (MLKL). Ferroptosis and necroptosis play important roles in various diseases such as tissue injury, cancer, and neurodegenerative diseases. Due to the intricate architecture of the kidney, the convergence of multiple systemic pathogenic factors, and the interactive regulation of intercellular signaling pathways, renal diseases exhibit complex pathogenesis and present limited therapeutic interventions. Exploring cell death and the interactions between different forms of cell death is highly important for understanding the occurrence and development of kidney diseases and for finding new treatment strategies. Ferroptosis and necroptosis influence renal cell viability and contribute to the exacerbation of kidney injury via inflammatory responses and additional mechanisms. They share common initiating factors and intersecting signaling pathways in the context of kidney diseases, thereby synergistically intensifying the pathological progression of renal damage. This article describes the pathogenesis and pathophysiological roles of ferroptosis, necroptosis, and their interactions in kidney diseases such as AKI and CKD and elucidates the potential of inhibiting ferroptosis and necroptosis, or their combined inhibition, in the prevention and treatment of kidney diseases such as AKI and CKD. Keywords: ferroptosis, necroptosis, lipid peroxidation, kidney disease, cell death