SLC7A11/GPX4 Inactivation-Mediated Ferroptosis Contributes to the Pathogenesis of Triptolide-Induced Cardiotoxicity

Oxid Med Cell Longev. 2022 Jun 16;2022:3192607. doi: 10.1155/2022/3192607. eCollection 2022.

Abstract

Triptolide exhibits promising efficacy in various cancers and immune diseases while its clinical application has been strongly restricted by its severe side effects, especially cardiotoxicity. However, the underlying mechanism of triptolide-induced cardiotoxicity (TIC) remains unclear. The RNA-seq analysis of triptolide-injured AC16 human cardiomyocyte cell line hinted that ferroptosis is involved in TIC. Further experimental validations proved that triptolide triggered ferroptosis, as evidenced by significant accumulation of lipid peroxidation (4-HNE and MDA levels) and ferrous iron, as well as depletion of intracellular GSH. Furthermore, triptolide-induced iron overload involved the upregulation of TF/TRFC/DMT1 signal axis and the degradation of ferritin, which contribute to ROS generation via Fenton reaction. In addition, inhibition of the antioxidant Nrf2/HO-1 pathway was observed in TIC, which may also lead to the overproduction of lethal lipid peroxides. Mechanistically, using streptavidin-biotin affinity pull-down assay and computational molecular docking, we unveiled that triptolide directly binds to SLC7A11 to inactivate SLC7A11/GPX4 signal axis. More importantly, employment of a ferroptosis inhibitor Ferrostatin-1 alleviated TIC by partially reversing the inhibitory effects of triptolide on SLC7A11/GPX4 signal. Altogether, our study demonstrated that SLC7A11/GPX4 inactivation-mediated ferroptosis contributed to the pathogenesis of TIC. Combating ferroptosis may be a promising therapeutic avenue to prevent TIC.

MeSH terms

  • Amino Acid Transport System y+ / metabolism
  • Cardiotoxicity* / metabolism
  • Diterpenes / pharmacology
  • Epoxy Compounds / pharmacology
  • Ferroptosis* / drug effects
  • Humans
  • Molecular Docking Simulation
  • Phenanthrenes* / pharmacology
  • Phospholipid Hydroperoxide Glutathione Peroxidase* / metabolism

Substances

  • Amino Acid Transport System y+
  • Diterpenes
  • Epoxy Compounds
  • Phenanthrenes
  • SLC7A11 protein, human
  • triptolide
  • Phospholipid Hydroperoxide Glutathione Peroxidase