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<p>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&#xa0;C proteinase (3C<sup>pro</sup>) 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 3C<sup>pro</sup> and 3D in activating ferroptotic pathways and presenting potential targets for therapeutic intervention in SVV infections.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • Jiangwei Song,
  • Jingjing Yang,
  • Ruiyi Ma,
  • Zijian Li,
  • Jiayao Su,
  • Shijie Xie,
  • Peipei Cheng

摘要

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.