安徽医科大学孟晓明团队近日取得一项新成果。经过不懈努力，他们的研究发现Cpd-A1通过抑制铁死亡减轻急性肾损伤。这一研究成果发表在2024年4月19日出版的国际学术期刊《中国药理学报》上。

在本研究中，设计并合成了具有优良血浆稳定性的Fer-1类似物(Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3)，并评估了它们在治疗急性肾损伤(AKI)中的治疗潜力。在药代动力学分析中，与Fer-1相比，它们的类似物在单核细胞肾组织中的分布更高，并且对铁死亡诱导剂处理的小鼠管状上皮细胞(mTECs)具有更有效的铁死亡抑制作用，其中以Cpd-A1最有效。

在缺氧/再氧化(H/R)或脂多糖处理的小鼠管状上皮细胞中，用Cpd-A1 (0.25μM)治疗可有效减轻细胞损伤，减轻炎症反应，并抑制铁死亡。在缺血/再灌注(I/R)或盲肠结扎穿刺(CLP)诱导的AKI模型中，预注射Cpd-A1(1.25、2.5、5.5 mg·kg^-1·d^-1, i.p)可以剂量依赖性改善肾功能，减轻肾小管损伤，消除炎症。研究团队得出结论，Cpd-A1可能作为一种有前景的治疗AKI的药物。

研究人员表示，急性肾损伤(AKI)被定义为以血清肌酐水平升高和尿量减少为特征的肾功能突然丧失，持续7天。铁死亡是一种铁依赖性的坏死途径，与AKI的进展有关，而铁抑制素-1 (Fer1)，一种选择性铁死亡抑制剂，在AKI模型中抑制肾损伤、氧化应激和肾小管细胞死亡。然而，由于Fer1缺乏疗效和代谢不稳定，其临床应用受到限制。

附：英文原文

Title: Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis

Author: 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

Issue&Volume: 2024-04-19

Abstract: 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 (0.25μM) 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, 5mg·kg1·d1, 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.

DOI: 10.1038/s41401-024-01277-w

Source: https://www.nature.com/articles/s41401-024-01277-w