Targeting the RNA acetyltransferase NAT10 attenuates pulmonary fibrosis via the ac4C-mediated regulation of the C/EBPβ-ITGA11 axis.

Abstract

Identifying novel therapeutic targets is urgent for idiopathic pulmonary fibrosis (IPF), a fatal disease with limited treatment options. N-acetyltransferase 10 (NAT10), the sole enzyme responsible for RNA N4-acetylcytidine (ac4C) modification, is implicated in diverse pathological processes. This study aimed to validate NAT10 as a potential therapeutic target for pulmonary fibrosis by utilizing the established small-molecule inhibitor, Remodelin, to functionally interrogate its role. We observed that NAT10 was significantly upregulated in lung tissues from IPF patients and bleomycin (BLM)-treated mice. Pharmacological blockade of NAT10 activity using Remodelin significantly attenuated lung structural destruction and collagen deposition in vivo. In vitro, inhibiting NAT10 function suppressed fibroblast activation and extracellular matrix production. Mechanistically, rather than directly modifying effector molecules, NAT10 stabilized the mRNA of transcription factor C/EBPβ via ac4C modification. This stabilization led to the transcriptional upregulation of Integrin α11 (ITGA11), thereby promoting fibroblast activation. Rescue experiments confirmed that the pro-fibrotic effects of NAT10 are dependent on this C/EBPβ-ITGA11 axis via its acetyltransferase activity. Collectively, our findings characterize NAT10 as a key pathogenic driver and demonstrate that inhibition of this epigenetic regulator offers a promising therapeutic strategy for ameliorating pulmonary fibrosis.