Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis

• Published in: Acta pharmacologica Sinica 2024-08, Vol.45 (8), p.1673-1685
• Main Authors: Chen, Ying, Wu, Ming-fei, Xie, Man-man, Lu, Yang, Li, Chao, Xie, Shuai-shuai, Ma, Wen-xian, Ji, Ming-lu, Hou, Rui, Dong, Ze-hui, He, Ruo-bing, Zhang, Meng-meng, Lu, Hao, Gao, Li, Wen, Jia-gen, Jin, Juan, Dong, Xiao-wu, Che, Jin-xin, Meng, Xiao-ming
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Cyclohexylamines - pharmacology; Cyclohexylamines - therapeutic use; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Ferroptosis - drug effects; Immunology; Internal Medicine; Male; Medical Microbiology; Mice; Mice, Inbred C57BL; Pharmacology/Toxicology; Phenylenediamines - pharmacology; Phenylenediamines - therapeutic use; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Vaccine
• ISSN: 1671-4083; 1745-7254; 1745-7254
• DOI: 10.1038/s41401-024-01277-w

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 μM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg −1 ·d −1 , i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.