tetano
Editor, Senior Moderator
Biochem Pharmacol
. 2026 Apr 25:118007.
doi: 10.1016/j.bcp.2026.118007. Online ahead of print.
4-Octyl itaconate blocks STAT3-induced ACE2 expression to reduce uptake of SARS-CoV-2
Hauke J Weiss[SUP] 1 [/SUP], Alexander Hooftman[SUP] 2 [/SUP], Clarisse Salgado-Benvindo[SUP] 3 [/SUP], Robbert Boudewijns[SUP] 4 [/SUP], Laurens Liesenborghs[SUP] 5 [/SUP], Tristram A J Ryan[SUP] 2 [/SUP], Demi van der Horst[SUP] 6 [/SUP], Madalina E Carter-Timofte[SUP] 6 [/SUP], Hossam Gewaid[SUP] 2 [/SUP], Andrew Bowie[SUP] 2 [/SUP], Hendrik Jan Thibaut[SUP] 7 [/SUP], Kai Dallmeier[SUP] 4 [/SUP], David Olagnier[SUP] 6 [/SUP], Martijn J van Hemert[SUP] 3 [/SUP], Luke A J O'Neill[SUP] 2 [/SUP]
Affiliations
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.
Keywords: ACE2; Antiviral response; Immuno metabolism; Itaconate; JAK-STAT-pathway; SARS-CoV-2.
. 2026 Apr 25:118007.
doi: 10.1016/j.bcp.2026.118007. Online ahead of print.
4-Octyl itaconate blocks STAT3-induced ACE2 expression to reduce uptake of SARS-CoV-2
Hauke J Weiss[SUP] 1 [/SUP], Alexander Hooftman[SUP] 2 [/SUP], Clarisse Salgado-Benvindo[SUP] 3 [/SUP], Robbert Boudewijns[SUP] 4 [/SUP], Laurens Liesenborghs[SUP] 5 [/SUP], Tristram A J Ryan[SUP] 2 [/SUP], Demi van der Horst[SUP] 6 [/SUP], Madalina E Carter-Timofte[SUP] 6 [/SUP], Hossam Gewaid[SUP] 2 [/SUP], Andrew Bowie[SUP] 2 [/SUP], Hendrik Jan Thibaut[SUP] 7 [/SUP], Kai Dallmeier[SUP] 4 [/SUP], David Olagnier[SUP] 6 [/SUP], Martijn J van Hemert[SUP] 3 [/SUP], Luke A J O'Neill[SUP] 2 [/SUP]
Affiliations
- PMID: 42044812
- DOI: 10.1016/j.bcp.2026.118007
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.
Keywords: ACE2; Antiviral response; Immuno metabolism; Itaconate; JAK-STAT-pathway; SARS-CoV-2.