2. Academic Validation
  3. Ferroptosis promotes valproate-induced liver steatosis in vitro and in vivo

Ferroptosis promotes valproate-induced liver steatosis in vitro and in vivo

  • Food Chem Toxicol. 2024 Aug 13:192:114926. doi: 10.1016/j.fct.2024.114926.
Xinrui Yan 1,  Linfeng Ma 2,  Xue Chen 1,  Jing Ren 1,  Yu Zhai 1,  Ting Wu 1,  Yu Song 3,  Xiaojiao Li 4,  Yingjie Guo 5
Affiliations

Affiliations

  • 1 School of Life Science, Jilin University, Changchun, 130012, China.
  • 2 Department of Medicine, Shandong College of Traditional Chinese Medicine, Yantai, Shandong, 264199, China; Department of Clinical Laboratory, Qingdao University Medical College Affiliated Yantai Yuhuangding Hospital, Yantai, 264099, China.
  • 3 Yazhou Bay Innovation Institute, Hainan Key Laboratory for Conservation and Utilization of Tropical Marine Fishery Resources, Key Laboratory of Utilization and Conservation for Tropical Marine Bioresources of Ministry of Education, College of Fisheries and Life Sciences, Hainan Tropical Ocean University, Sanya, 572022, China.
  • 4 Phase I Clinical Trial Center, The First Hospital of Jilin University, Changchun, 130021, China. Electronic address: xiaojiaoli@jlu.edu.cn.
  • 5 School of Life Science, Jilin University, Changchun, 130012, China. Electronic address: guoyingjie@jlu.edu.cn.
PMID: 39147356 DOI: 10.1016/j.fct.2024.114926
Abstract

Valproic acid (VPA), a common antiepileptic drug, can cause liver steatosis after long-term therapy. However, an impact of Ferroptosis on VPA-induced liver steatosis has not been investigated. In the study, treatment with VPA promoted Ferroptosis in the livers of mice by elevating ferrous iron (Fe2+) levels derived from the increased absorption by Transferrin Receptor 1 (TFR1) and the decreased storage by ferritin (FTH1 and FTL), disrupting the redox balance via reduced levels of solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), and Glutathione Peroxidase 4 (GPX4), and augmenting acyl-CoA synthetase long-chain family member 4 (ACSL4) -mediated lipid peroxide generation, accompanied by enhanced liver steatosis. All the changes were significantly reversed by co-treatment with an iron-chelating agent, deferoxamine mesylate (DFO) and a Ferroptosis inhibitor, ferrostatin-1 (Fer-1). Similarly, the increases in Fe2+, TFR1, and ACSL4 levels, as well as the decreases in GSH, GPX4, and Ferroportin (FPN) levels, were detected in VPA-treated HepG2 cells. These changes were also attenuated after co-treatment with Fer-1. It demonstrates that Ferroptosis promotes VPA-induced liver steatosis through iron overload, inhibition of the GSH-GPX4 axis, and upregulation of ACSL4. It offers a potential therapy targeting Ferroptosis for patients with liver steatosis following VPA treatment.

Keywords

Ferroptosis; Iron overload; Lipid peroxidation; Liver steatosis; Valproate.

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