NAT10-mediated lipid metabolic reprogramming drives EGFR-TKI resistance in non-small cell lung cancer via ac4C-dependent mRNA stabilization.

The development of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment represents a significant challenge to targeted therapies for lung cancer. To explore the feasibility of epigenetic therapy in overcoming resistance, an epigenetic drug library was screened, identifying Remodelin as a potent enhancer of EGFR-TKI sensitivity in non-small cell lung cancer (NSCLC) cells. We demonstrated that the cytidine acetyltransferase NAT10 was overexpressed in NSCLC tissues and was associated with poor patient prognosis. NAT10 knockdown inhibited proliferation, increased apoptosis, and enhanced sensitivity to EGFR-TKIs both in vitro and in vivo. Mechanistically, NAT10 promoted EGFR-TKI resistance in NSCLC by remodeling fatty acid metabolism. Specifically, NAT10 was found to promote ac4C modification of fatty acid transport protein 4 (FATP4) and carnitine palmitoyltransferase 1 A (CPT1A) mRNAs, leading to increased stability and expression of these genes. Furthermore, p300-mediated H3K27ac acetylation was found to be a critical upstream regulator of NAT10 transcription. In vivo, mouse xenograft models confirmed that Remodelin significantly enhanced the antitumor efficacy of gefitinib. These findings suggest the potential of NAT10 as a therapeutic target to overcome EGFR-TKI resistance and improve treatment outcomes in patients with NSCLC.