Cis-aconitate therapy protects against influenza mortality by dual targeting of viral polymerase and ERK/AKT/NF-κB signaling
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.
Authors
- Thomas Baranek (ORCID: https://orcid.org/0000-0002-5651-0937)
- Arnaud Machelart (ORCID: https://orcid.org/0000-0002-4444-0011)
- Laure Perrin‐Cocon (ORCID: https://orcid.org/0000-0003-0501-6733)
- Alan Wacquiez (ORCID: https://orcid.org/0000-0001-5266-5328)
- Damien Sizaret (ORCID: https://orcid.org/0009-0009-8021-0342)
- Cyrille Mathieu (ORCID: https://orcid.org/0000-0002-6682-2029)
- François Trottein (ORCID: https://orcid.org/0000-0003-3373-1814)
- Adeline Cezard (ORCID: https://orcid.org/0000-0001-8608-701X)
- Virginie Vasseur
- Ronan Le Goffic (ORCID: https://orcid.org/0000-0002-2012-0064)
- Vincent Lotteau (ORCID: https://orcid.org/0000-0003-0997-3282)
- Lola Canus (ORCID: https://orcid.org/0009-0005-8061-4786)
- Delphine Fouquenet
- Julien Burlaud‐Gaillard (ORCID: https://orcid.org/0000-0001-5171-9873)
- Christophe Paget (ORCID: https://orcid.org/0000-0002-5374-5407)
- Antoine GUILLON
- Florentine Jacolin (ORCID: https://orcid.org/0009-0000-5527-8323)
- Si-Tahar Mustapha
- Ambre Tinard
- Michael G. Surette
- Antoine Legras
- Pierre-Olivier Vidalain
- Loic Gonzalez
- Bruno Da Costa
- Déborah Brea-Diakite
- Séverine Heumel
- Priscille Brodin
- Eik Hoffmann
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Université de Tours (FR)
- École Normale Supérieure de Lyon (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Versailles Saint-Quentin-en-Yvelines (FR)
- Université Paris-Saclay (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Centre Hospitalier Universitaire de Tours (FR)
- Center for Infection and Immunity of Lille (FR)
- Clinical Investigation Center Plurithematic Tours (FR)
- Virologie et Immunologie Moléculaires (FR)
- Centre d'Étude des Pathologies Respiratoires (FR)
- McMaster University (CA)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-02-16
- DOI
- https://doi.org/10.1038/s44321-026-00379-8
- Citations
- 1
- Primary Topic
- Influenza Virus Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 31.52
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Universiteit Leiden
- Leids Universitair Medisch Centrum