2. Academic Validation
  3. Chemical screen in zebrafish lateral line identified compounds that ameliorate neomycin-induced ototoxicity by inhibiting ferroptosis pathway

Chemical screen in zebrafish lateral line identified compounds that ameliorate neomycin-induced ototoxicity by inhibiting ferroptosis pathway

  • Cell Biosci. 2024 Jun 5;14(1):71. doi: 10.1186/s13578-024-01258-w.
Yipu Fan # 1 2 3,  Yihan Zhang # 4,  Dajiang Qin 1 4 5,  Xiaodong Shu 6 7
Affiliations

Affiliations

  • 1 Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China.
  • 2 Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
  • 3 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510005, China.
  • 5 Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510700, China.
  • 6 Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. shu_xiaodong@gibh.ac.cn.
  • 7 School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, 310023, China. shu_xiaodong@gibh.ac.cn.
  • # Contributed equally.
PMID: 38840194 DOI: 10.1186/s13578-024-01258-w
Abstract

Background: Ototoxicity is a major side effect of many broadly used Aminoglycoside antibiotics (AGs) and no FDA-approved otoprotective drug is available currently. The zebrafish has recently become a valuable model to investigate AG-induced hair cell toxicity and an expanding list of otoprotective compounds that block the uptake of AGs have been identified from zebrafish-based screening; however, it remains to be established whether inhibiting intracellular cell death pathway(s) constitutes an effective strategy to protect against AG-induced ototoxicity.

Results: We used the zebrafish model as well as in vitro cell-based assays to investigate AG-induced cell death and found that Ferroptosis is the dominant type of cell death induced by neomycin. Neomycin stimulates lipid Reactive Oxygen Species (ROS) accumulation through mitochondrial pathway and blocking mitochondrial Ferroptosis pathway effectively protects neomycin-induced cell death. We screened an alkaloid natural compound library and identified seven small compounds that protect neomycin-induced ototoxicity by targeting Ferroptosis pathway: six of them are radical-trapping agents (RTAs) while the other one (ellipticine) regulates intracellular iron homeostasis, which is essential for the generation of lipid ROS to stimulate Ferroptosis.

Conclusions: Our study demonstrates that blocking intracellular Ferroptosis pathway is an alternative strategy to ameliorate neomycin-induced ototoxicity and provides multiple hit compounds for further otoprotective drug development.

Keywords

Aminoglycoside; Ferroptosis; Neomycin; Ototoxicity; Zebrafish.

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