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  3. A novel 3-phenylglutaric acid derivative (84-B10) alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial ROS-mediated ferroptosis

A novel 3-phenylglutaric acid derivative (84-B10) alleviates cisplatin-induced acute kidney injury by inhibiting mitochondrial ROS-mediated ferroptosis

  • Free Radic Biol Med. 2022 Nov 17;S0891-5849(22)00992-3. doi: 10.1016/j.freeradbiomed.2022.11.029.
Jiaojiao Fan 1,  Xinyue Xu 1,  Yuting Li 2,  Lingge Zhang 2,  Mengqiu Miao 3,  Yujia Niu 4,  Yue Zhang 5,  Aihua Zhang 6,  Zhanjun Jia 7,  Mengqiu Wu 8
Affiliations

Affiliations

  • 1 School of Medicine, Southeast University, Nanjing, 210009, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China.
  • 2 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
  • 3 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China.
  • 4 Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China.
  • 5 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China.
  • 6 School of Medicine, Southeast University, Nanjing, 210009, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. Electronic address: [email protected].
  • 7 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. Electronic address: [email protected].
  • 8 Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China. Electronic address: [email protected].
PMID: 36403736 DOI: 10.1016/j.freeradbiomed.2022.11.029
Abstract

Cisplatin is one of the most effective chemotherapy drugs and is widely used for Cancer treatment. However, its clinical use is limited by nephrotoxicity. Emerging findings suggested that both Ferroptosis and mitochondrial dysfunction mediate cisplatin-induced nephrotoxicity. In the current study, a novel 3-phenylglutaric acid derivative 5-[[2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl]amino]-5-oxo-3-phenylpentanoic acid (referred to as 84-B10) was found to play a protective role in cisplatin-induced acute kidney injury with no tumor promoting effects. A genome-wide transcriptome analysis indicated that the protective effect of 84-B10 might be dependent on antagonizing Ferroptosis. In accordance, lipid peroxide accumulation and downregulation of key Ferroptosis suppressors were reversed using 84-B10 treatment both in vivo and in vitro. In addition, 84-B10 inhibited cisplatin-induced mitochondrial damage and mitochondrial Reactive Oxygen Species (mtROS) production and restored superoxide dismutases (SODs). Furthermore, 84-B10 showed similar therapeutic effects to MnTBAP (a cell-permeable SOD mimetic) in eliminating mtROS, restoring mitochondrial homeostasis, and inhibiting Ferroptosis under cisplatin challenge. Comparable effects of 84-B10 and liproxstatin-1 in ameliorating cisplatin-induced Ferroptosis were observed. However, liproxstatin-1 failed to prevent mitochondrial dysfunction. These data indicated that mtROS might act upstream of cisplatin-induced tubular Ferroptosis. Taken together, the novel 3-phenylglutaric acid derivative 84-B10 showed therapeutic potential against cisplatin-induced nephrotoxicity possibly by restoring mitochondria homeostasis and inhibiting mtROS-induced Ferroptosis, which suggests the potential use of 84-B10 in preventing and treating cisplatin-nephrotoxicity.

Keywords

84-B10; Acute kidney injury; Ferroptosis; Liproxstatin-1; Mitochondrial ROS; MnTBAP.

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