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<p>The influenza virus poses a significant global health challenge, causing approximately 500,000 deaths annually. Its ability to evade antiviral treatments and vaccine-induced immunity underscores the need for novel therapeutic approaches. Our study identifies <i>cis</i>-aconitate (<i>cis</i>-aco), a mitochondria-derived metabolite, as a potent dual-action agent against influenza, independently of its metabolic derivative, itaconate. <i>Cis</i>-aco impairs viral polymerase activity, resulting in decreased viral mRNA expression and protein synthesis, as observed for the influenza A/Scotland/20/74 (H3N2) strain. This antiviral effect was further confirmed across multiple influenza A and B strains, as well as in ex vivo human airway and lung organotypic models. Beyond its antiviral properties, <i>cis-</i>aco exhibits potent anti-inflammatory effects, disrupting key inflammatory cascades and reducing the secretion of inflammatory mediators. In a mouse model of influenza pneumonia, <i>cis</i>-aco mitigates viral replication, inflammation, and immune cell activation, significantly improving survival. Notably, its efficacy persists even when administered at later stages of infection, when oseltamivir/Tamiflu® is no longer effective. These findings position <i>cis</i>-aco as a promising influenza treatment, combining antiviral and anti-inflammatory benefits within a clinically relevant timeframe.</p>

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Cis-aconitate therapy protects against influenza mortality by dual targeting of viral polymerase and ERK/AKT/NF-κB signaling

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月16日

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  • Adeline Cezard,
  • Déborah Brea-Diakite,
  • Virginie Vasseur,
  • Alan Wacquiez,
  • Loic Gonzalez,
  • Ronan Le Goffic,
  • Bruno Da Costa,
  • Ambre Tinard,
  • Delphine Fouquenet,
  • Séverine Heumel,
  • Arnaud Machelart,
  • Eik Hoffmann,
  • Priscille Brodin,
  • François Trottein,
  • Cyrille Mathieu,
  • Lola Canus,
  • Florentine Jacolin,
  • Pierre-Olivier Vidalain,
  • Laure Perrin-Cocon,
  • Vincent Lotteau,
  • Julien Burlaud-Gaillard,
  • Dominique Tertigas,
  • Michael G Surette,
  • Antoine Legras,
  • Damien Sizaret,
  • Thomas Baranek,
  • Christophe Paget,
  • Antoine Guillon,
  • Mustapha Si-Tahar

摘要

The influenza virus poses a significant global health challenge, causing approximately 500,000 deaths annually. Its ability to evade antiviral treatments and vaccine-induced immunity underscores the need for novel therapeutic approaches. Our study identifies cis-aconitate (cis-aco), a mitochondria-derived metabolite, as a potent dual-action agent against influenza, independently of its metabolic derivative, itaconate. Cis-aco impairs viral polymerase activity, resulting in decreased viral mRNA expression and protein synthesis, as observed for the influenza A/Scotland/20/74 (H3N2) strain. This antiviral effect was further confirmed across multiple influenza A and B strains, as well as in ex vivo human airway and lung organotypic models. Beyond its antiviral properties, cis-aco exhibits potent anti-inflammatory effects, disrupting key inflammatory cascades and reducing the secretion of inflammatory mediators. In a mouse model of influenza pneumonia, cis-aco mitigates viral replication, inflammation, and immune cell activation, significantly improving survival. Notably, its efficacy persists even when administered at later stages of infection, when oseltamivir/Tamiflu® is no longer effective. These findings position cis-aco as a promising influenza treatment, combining antiviral and anti-inflammatory benefits within a clinically relevant timeframe.