NRF2 activators inhibit influenza A virus replication by interfering with nucleo-cytoplasmic export of viral RNPs in an NRF2-independent manner.
Level 5 - mechanism / opinion, no new human data
Bench research (in vitro human cell cultures and in silico computational modeling).
PubMed 37459366 · doi:10.1371/journal.ppat.1011506
What was done
Researchers evaluated the antiviral activity of three electrophilic NRF2 activators (4-octyl itaconate [4OI], bardoxolone methyl [BARD], and sulforaphane [SFN]) alongside the exportin-1 (XPO1) inhibitor selinexor (SEL) against influenza A virus (A/Puerto Rico/8/1934 H1N1) in cultured human A549, vascular endothelial, and Calu3 cells. They measured viral titers in supernatants, nucleo-cytoplasmic export of viral nucleoprotein (NP) and host p53, and intracellular viral HA mRNA and NP levels. To dissect the pathway, they used KEAP1 knockdown, NFE2L2 (NRF2) knockout, XPO1 knockdown, an alkynated 4OI probe to assess direct covalent XPO1 binding, and computational ligand-target modeling against XPO1 (Cys528) and KEAP1 (Cys151).
What was found
No exact quantitative values (such as IC50s, log-titer drops, or binding energies) were reported in the abstract. All tested compounds reduced viral titers in cell supernatants with a relative efficacy order of SEL > 4OI > BARD = SFN. This inhibition correlated with blocked nucleo-cytoplasmic export of viral NP and p53, without altering intracellular viral HA mRNA or NP levels. While baseline NRF2 signaling restricted viral replication, the antiviral effects of the compounds were NRF2-independent. Instead, XPO1 knockdown reduced viral titers, 4OI covalently bound XPO1, and modeling predicted covalent binding of all four compounds to Cys528 of XPO1 as well as Cys151 of KEAP1.
Why it matters
This study identifies a noncanonical, NRF2-independent mechanism showing that electrophilic NRF2 activators directly inhibit XPO1-mediated nuclear export. This opens potential avenues for developing dual-action therapeutics combining host cytoprotection with nuclear export blockade against viruses.
Limits
The study is entirely in vitro and in silico, with no in vivo animal or human validation. Testing was restricted to a single lab-adapted H1N1 strain, and the abstract omits quantitative effect sizes, IC50 concentrations, and cytotoxicity measurements.
Cited by
- supports There are published scientific papers demonstrating direct antiviral effects of sulforaphane.