2. Academic Validation
  3. Epothilone B inactivation of Sirtuin1 promotes mitochondrial reactive oxygen species to induce dysfunction and ferroptosis of Schwann cells

Epothilone B inactivation of Sirtuin1 promotes mitochondrial reactive oxygen species to induce dysfunction and ferroptosis of Schwann cells

  • Eur J Pharm Sci. 2022 Dec 7;106350. doi: 10.1016/j.ejps.2022.106350.
Zhuowen Liang 1,  Na Zhang 1,  Xuankang Wang 1,  Jiawei Zhang 1,  Kun Li 2,  Tao Lei 3
Affiliations

Affiliations

  • 1 Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 2 Xijing Orthopaedics Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: [email protected].
  • 3 Department of Biomedical Engineering, School of Biomedical Engineering, Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: [email protected].
PMID: 36496165 DOI: 10.1016/j.ejps.2022.106350
Abstract

Epothilone B (EpoB) is an FDA-approved anti-neoplastic agent used to treat metastatic breast cancer; However, its usage is limited due to its severe peripheral neurotoxicity. Ferroptosis is a type of programmed cell death triggered by iron accumulation, and it is induced by lipid peroxidation. Ferroptosis has been linked to multiple diseases, including Cancer, type 2 diabetes, and neurodegenerative disorders. Here, we assessed the role of Ferroptosis in EpoB-induced neural dysfunction. Our results revealed that EpoB induced Ferroptosis, which was significantly reduced by the Ferroptosis inhibitor Fer-1. In addition, EpoB decreased the mitochondrial membrane potential and the cytochrome c levels in Schwann cells (SCs). The antioxidant MitoTEMPO, which targets the mitochondria, reduced Ferroptosis brought on by EpoB. Moreover, we demonstrated that in vivo EpoB-induced myelin degradation and neuronal dysfunction were mitigated by SRT1720, a Sirtuin1 (SIRT1) activator, and by SRT1720 and mitoquinone mesylate (mitoQ). Our results suggest that Ferroptosis elicited by EpoB is caused by mitochondrial damage mediated by SIRT1 inactivation and that Ferroptosis causes neural dysfunction following EpoB.

Keywords

EpoB; Ferroptosis; Mitochondria; Neural dysfunction; SIRT1.

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