Discovery of THB Derivates as Ferroptosis Inhibitors for the Treatment of Acute Kidney Injury by Targeting VDAC

  • J Med Chem. 2025 Jun 12;68(11):11340-11364. doi: 10.1021/acs.jmedchem.5c00280.
Shengkuan Peng  1 ,  Wenhao Zhang  2 ,  Qiaoyi Sun  1 ,  Wenqiang Zhang  1 ,  Yadong Chen  1 ,  Zhicheng Lv  3 ,  Zhihang Fang  3 ,  Xian Wei  4 ,  Tao Lu  1 ,  Guo Chen  2 ,  Yu Jiao  1
Affiliations
  • 1. School of Science, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 2. School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 3. School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 4. Department of Pharmacy, Youjiang Medical University for Nationalities, Baise 533000, P. R. China.
PMID: 40402184 DOI: 10.1021/acs.jmedchem.5c00280
Abstract

Acute kidney injury (AKI), a clinical syndrome marked by high morbidity and mortality, remains a significant challenge due to the lack of effective therapeutic options. The accumulation of Fe2+ and Reactive Oxygen Species (ROS) in injured renal cells, which triggers Ferroptosis, play a key driver in the pathogenesis of AKI. In this study, tetrahydroberberine (THB), a natural product, was identified as a Ferroptosis inhibitor that targeted the voltage-dependent anion channel (VDAC). Through structural optimization, a series of THB derivatives were developed, among which 34a exhibited about 100-fold enhanced Ferroptosis inhibitory activity. Moreover, 34a significantly reduced ROS, Fe2+ and restored glutathione (GSH) below 20 nM. In vivo experiments confirmed that 34a effectively alleviated folic acid-induced AKI, accompanied by a reduction in key kidney injury markers. These results highlight the potential of 12-amino THB derivatives as novel Ferroptosis inhibitors and provide promising therapeutic strategies for AKI treatment.

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