1. Academic Validation
  2. Trastuzumab-induced cardiomyopathy via ferroptosis-mediated mitochondrial dysfunction

Trastuzumab-induced cardiomyopathy via ferroptosis-mediated mitochondrial dysfunction

  • Free Radic Biol Med. 2023 Jun 29;S0891-5849(23)00506-3. doi: 10.1016/j.freeradbiomed.2023.06.019.
Ting Ye 1 Wei Yang 2 Tielei Gao 3 Xue Yu 1 Tianzuo Chen 1 Yan Yang 1 Jinxiang Guo 1 Quanfeng Li 1 Hong Li 4 Liming Yang 5
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150081, China.
  • 2 Department of Pathophysiology, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150081, China; School of Public Health, Qiqihar Medical University, Qiqihar, China.
  • 3 Department of Forensic Medicine, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150081, China.
  • 4 Department of Pathophysiology, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, 150081, China. Electronic address: drlihong1971@163.com.
  • 5 Department of Pathophysiology, Harbin Medical University (Daqing), 39 Xinyang Road, Gaoxin District, Daqing, 163319, China. Electronic address: limingyang@ems.hrbmu.edu.cn.
Abstract

Trastuzumab (TRZ) is a first-line chemotherapeutic agent for HER-2 (ErbB2)-positive breast Cancer. Unfortunately, its clinical use is limited due to its cardiotoxicity, referred to as TRZ-induced cardiotoxicity (TIC). However, the exact molecular mechanisms underlying the development of TIC remain unclear. Iron and lipid metabolism and redox reactions participate in the development of Ferroptosis. Here, we show that ferroptosis-mediated mitochondrial dysfunction is involved in TIC in vivo and in vitro. We first established TIC models with BALB/c mice or neonatal rat cardiomyocytes and confirmed cardiomyopathy with echocardiography and inhibition of cell viability with a cell counting kit-8 examination, respectively. We showed that TRZ downregulated Glutathione Peroxidase 4 (GPx4) and elevated lipid peroxidation by-products, 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), by inactivating the ErbB2/PI3K/Akt/Nrf2 signalling pathway. Additionally, upregulated mitochondrial 4-HNE binds to voltage-dependent anion channel 1 (VDAC1), increases VDAC1 oligomerization, and subsequently induces mitochondrial dysfunction, as evidenced by mitochondrial permeability transition pore (mPTP) opening and decreased mitochondrial membrane potential (MMP) and ATP levels. Concomitantly, TRZ affected the mitochondrial levels of GSH/GSSG and iron ions and the stability of mitoGPx4. Ferroptosis inhibitors, such as ferrostatin-1 (Fer-1) or iron chelators deferoxamine (DFO), ameliorate TRZ-induced cardiomyopathy. Overexpression of mitoGPx4 also suppressed mitochondrial lipid peroxidation and prevented TRZ-induced Ferroptosis. Our study strongly suggests that targeting ferroptosis-mediated mitochondrial dysfunction is a potential cardioprotective strategy.

Keywords

Cardiomyopathy; Ferroptosis; Mitochondrial dysfunction; Trastuzumab.

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