Researchers discovered that the enzyme NAT10 is dramatically upregulated in macrophages exposed to bacterial endotoxin (LPS). This upregulation is driven by the deubiquitinase USP39, which prevents NAT10 protein from being degraded. NAT10 then adds ac4C chemical tags to mRNA of the transcription factor ETS2, boosting its stability and translation and amplifying a pro-inflammatory cytokine storm. In mice with endotoxemia, deleting NAT10 specifically in myeloid cells — or pharmacologically inhibiting it with the drug remodelin — significantly reduced inflammation and preserved heart function. The findings identify a novel post-transcriptional regulatory axis and suggest NAT10 as a druggable target for sepsis-induced cardiac dysfunction.
