A renewed perspective on TCA intermediate cis-aconitate: mechanisms and therapeutic options against influenza virus

Effective therapeutic strategies for influenza, ranging from seasonal flu outbreaks to sporadic pandemics, should ideally combine antiviral efficacy to accelerate viral clearance with targeted immunomodulation to mitigate excessive inflammation. In this issue of EMBO Molecular Medicine, Cezard et al introduce the inhibitory potential of the tricarboxylic acid (TCA) cycle intermediate cis-aconitate against influenza virus. Cis-aconitate is promising for further translational evaluation, as it meets the dual targeting criteria of antiviral and anti-inflammatory activity at both early as well as late stages of infection. Remarkably, these effects occur independently of its conversion into itaconate, a well-characterized immunomodulatory TCA derivative. This novel aspect of cis-aconitate further supports continued consideration of TCA cycle intermediates beyond their canonical metabolic roles. C. Claus and I. Kovacevic discuss the identification of cis-aconitate, a mitochondria-derived metabolite, with dual antiviral and anti-inflammatory activity against influenza, as reported by M. Si-Tahar and colleagues, in this issue of EMBO Mol Med.