4-Octyl itaconate blocks STAT3-induced ACE2 expression to reduce uptake of SARS-CoV-2

Itaconate is a Krebs cycle-derived metabolite with anti-inflammatory and antiviral properties. This particularly applies to derivatives of itaconate, notably 4-octyl itaconate (4-OI), which has been extensively studied in models of inflammation and infection. Itaconate and 4-OI have been shown to exhibit antiviral activity against Zika virus, Influenza A virus (IAV) and Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Here we have further analysed the effect of itaconate and 4-OI on SARS-CoV-2 infection. 4-OI inhibited replication of SARS-CoV-2 in vitro and in vivo, in agreement with recent literature. In lung epithelial cells, 4-OI potently blocked expression of the SARS-CoV-2 uptake receptor, Angiotensin-converting enzyme 2 (ACE2), reducing ACE2 dependent uptake of viral pseudo particles. 4-OI inhibited the induction of both a truncated version of ACE2 and signal transducer and activator of transcription 3 (STAT3)-dependent full-length ACE2, possibly because of its inhibitory effect on Janus kinase 1 (JAK1). Inhibition of JAK1 by 4-OI will therefore block ACE2 expression as well as other effects driven by JAK1, highlighting a dual capability of itaconate derivatives such as 4-OI for having antiviral and anti-inflammatory effects, which could have therapeutic utility in COVID-19.