NAT10 promotes gallbladder cancer progression by remodeling cholesterol metabolism via PCSK9 mRNA acetylation

Abstract Gallbladder cancer (GBC) is a highly aggressive biliary tract tumor with a poor prognosis, underscoring the critical need for new therapeutic strategies. N-acetyltransferase 10 (NAT10), the sole writer of N4-acetylcytidine (ac4C), is upregulated in multiple cancers and is implicated in tumor pathogenesis. We observed significant NAT10 overexpression in GBC. Functional studies confirmed that NAT10 drives growth, migration, and malignant progression of GBC cells. We mechanistically linked this to NAT10-mediated ac4C modification, which stabilizes proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA, thereby reprogramming cholesterol metabolism and triggering intracellular cholesterol accumulation. This cholesterol buildup subsequently activates the PI3K/AKT pathway, stimulating cancer cell proliferation, migration, and invasion. Therapeutically, targeting NAT10 with Remodelin potently suppressed GBC proliferation. Importantly, Remodelin synergized with the standard chemotherapeutic agent gemcitabine to markedly enhance its therapeutic effect. Thus, our study defines a novel mechanism in which NAT10-dependent ac4C modification stabilizes PCSK9 mRNA to promote cholesterol-driven malignancy, nominating NAT10 as a compelling therapeutic target in GBC.