Network Pharmacology and Metabolomics Reveal Anti-Ferroptotic Effects of Curcumin in Acute Kidney Injury

Xi Liu,1,2,* Yu Zhou,3,* Ziyi Lu,1 Fenglin Yang,1 Yizhi Wang,4 Sijin Zhang,5 Jinwen Zhang,1 Hong Zou,6 Min Lin1 1Research Center of Innovation, Entrepreneurship, Minjiang University, Fuzhou, 350100, People’s Republic of China; 2Key Laboratory for Chemical Biology of Fujian Province, MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, People’s Republic of China; 3Cancer Research Center & Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, 330004, People’s Republic of China; 4School of Intelligent Science and Control Engineering, Jinling Institute of Technology, Nanjing, 211169, People’s Republic of China; 5Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510000, People’s Republic of China; 6Physical Education Department, Xiamen University, Xiamen, 361005, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min Lin; Hong Zou, Email [email protected]; [email protected]: Acute kidney injury (AKI) is linked to high rates of mortality and morbidity worldwide thereby posing a major public health problem. Evidences suggest that ferroptosis is the primary cause of AKI, while inhibition of monoamine oxidase A(MAOA) and 5-hydroxytryptamine were recognized as the defender of ferroptosis. Curcumin (Cur) is a natural polyphenol and the main bioactive compound of Curcuma longa, which has been found nephroprotection in AKI. However, the potential mechanism of Cur in alleviating AKI ferroptosis remains unknown.Objective: This study aims to investigate the effects of Cur on AKI ferroptosis.Methods: Folic acid (FA)-induced AKI mouse model and erastin/(rsl-3)-induced HK-2 model were constructed to assess the renoprotection of Cur. The nuclear magnetic resonance (NMR)-based metabolomics coupled network pharmacology approach was used to explore the metabolic regulation and potential targets of Cur. Molecular docking and enzyme activity assay was carried out to evaluate the effects of Cur on MAOA.Results: Our results showed that in vivo Cur preserved renal functions in AKI mice by lowering levels of serum creatinine, blood urea nitrogen, while in vitro ameliorated the cell viability of HK-2 cells damaged by ferroptosis. Mechanistic studies indicated that Cur protected AKI against ferroptosis via inhibition of MAOA thereby regulating 5-hydroxy-L-tryptophan metabolism.Conclusion: Our study for the first time clarified that Cur might acts as a MAOA inhibitor and alleviates ferroptosis in AKI mice, laying a scientific foundation for new insights of clinical therapy on AKI.Keywords: acute kidney injury, curcumin, network pharmacology, metabolomics, monoamine oxidase A, ferroptosis