2. Academic Validation
  3. ATF4 protects against sorafenib-induced cardiotoxicity by suppressing ferroptosis

ATF4 protects against sorafenib-induced cardiotoxicity by suppressing ferroptosis

  • Biomed Pharmacother. 2022 Sep;153:113280. doi: 10.1016/j.biopha.2022.113280.
Hui Jiang 1,  Cong Wang 2,  An Zhang 3,  Yufeng Li 4,  Jianping Li 4,  Zhan Li 5,  Xin Yang 4,  Yinglong Hou 6
Affiliations

Affiliations

  • 1 Department of Pediatrics, The Second Hospital of Shandong University, Jinan, Shandong 250033, China; Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China.
  • 2 Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China; Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, Jinan, Shandong 250014, China.
  • 3 Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China.
  • 4 Department of Pediatrics, The Second Hospital of Shandong University, Jinan, Shandong 250033, China.
  • 5 Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, Jinan, Shandong 250014, China.
  • 6 Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China; Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, Jinan, Shandong 250014, China. Electronic address: houyinglong2010@hotmail.com.
PMID: 35724508 DOI: 10.1016/j.biopha.2022.113280
Abstract

Sorafenib (SOR) is an effective chemotherapy drug for hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma. However, a long-standing clinical issue associated with SOR use is an increased risk of cardiotoxicity, but the underlying mechanisms remain obscure. Here we report that Ferroptosis of cardiomyocytes is responsible for SOR-induced cardiotoxicity. The specific Ferroptosis inhibitor ferrostatin-1 and deferoxamine mesylate, an iron chelator, significantly alleviate SOR-induced cardiac damage. RNA-sequencing revealed that endoplasmic reticulum (ER) stress and the unfolded protein response were predominately activated, which might be attributed to the lipid reactive oxygen species-mediated perturbation of the ER. Activating transcription factor 4 (ATF4) is one of the most significantly up-regulated genes, knockdown of ATF4 exacerbates cardiomyocyte Ferroptosis induced by SOR, while overexpression of ATF4 promotes cell survival. Mice with AAV-mediated ATF4 knockdown exhibit lipid peroxidation and more severe cardiomyopathy. Further experiments demonstrated that ATF4 exerts its protective role by elevating SLC7A11 expression, a transport subunit of system Xc-, which promotes cystine uptake and glutathione biosynthesis. The cardioprotective effect of ATF4 was diminished by SLC7A11 knockdown in cardiomyocytes subjected to SOR treatment. Taken together, these findings show that Ferroptosis of cardiomyocytes is an important cause of SOR-related cardiotoxicity. ATF4 acts as a key regulator to promote cardiomyocytes survival by up-regulation of SLC7A11 and suppression of Ferroptosis.

Keywords

Antineoplastic drugs; Cardiotoxicity; Endoplasmic reticulum stress; Ferroptosis.

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