2. Academic Validation
  3. Synergetic contributions of Seneca Valley virus 3 C and 3D proteins to induction of ferroptosis for viral replication

Synergetic contributions of Seneca Valley virus 3 C and 3D proteins to induction of ferroptosis for viral replication

  • Cell Mol Life Sci. 2025 Nov 14;82(1):406. doi: 10.1007/s00018-025-05951-y.
Jiangwei Song # 1,  Jingjing Yang # 2 3,  Ruiyi Ma # 2 4,  Zijian Li 2 3,  Jiayao Su 2 3,  Shijie Xie 2,  Peipei Cheng # 5
Affiliations

Affiliations

  • 1 Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, No. 9 Shuguan Garden Middle Road, Haidian District, Beijing, 100097, China. [email protected].
  • 2 Beijing Key Laboratory for Prevention and Control of Infectious Diseases in Livestock and Poultry, Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, No. 9 Shuguan Garden Middle Road, Haidian District, Beijing, 100097, China.
  • 3 College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China.
  • 4 College of Veterinary Medicine, Shanxi Agricultural University, Taigu, China.
  • 5 Beijing Biomedicine Technology Center, Zhaofeng Hua Biotechnology, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41236547 DOI: 10.1007/s00018-025-05951-y
Abstract

Seneca Valley virus (SVV) Infection leads to severe vesicular diseases in pigs, posing a significant threat to the global swine industry. Ferroptosis, a novel form of non-apoptotic cell death, is characterized by iron-dependent phospholipid peroxidation. However, the role of Ferroptosis in SVV replication remains poorly understood. In this study, we demonstrate that SVV Infection induces Ferroptosis, as evidenced by lipid peroxidation, Reactive Oxygen Species (ROS) accumulation, and glutathione (GSH) depletion. The GPX4 and nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy are key contributors to Ferroptosis induction. Furthermore, our findings reveal that the SVV 3 C proteinase (3Cpro) targets the GPX4 for degradation, thereby promoting Ferroptosis. Simultaneously, the SVV 3D protein enhances the NCOA4-FTH1 interaction, leading to increased ferritin degradation and subsequent ferritinophagy. Notably, inhibition of Ferroptosis significantly reduces SVV replication and its associated inflammatory effects. Collectively, these results elucidate the intricate molecular mechanisms underlying SVV-induced Ferroptosis, highlighting the synergistic roles of 3Cpro and 3D in activating ferroptotic pathways and presenting potential targets for therapeutic intervention in SVV infections.

Keywords

Ferritinophagy; Ferroptosis; GPX4; NCOA4; Seneca valley virus (SVV).

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