NAT10 drives hepatocellular carcinoma progression through SQLE-mediated cholesterol biosynthesis and is targetable by remodelin.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy characterized by a paucity of therapeutic options. An analysis of multi-omics datasets, including The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and the National Omics Data Encyclopedia (NODE) database, revealed that NAT10 is significantly upregulated in HCC and is associated with poor patient survival outcomes. Mechanistically, our findings demonstrate that NAT10 functions as an upstream activator of SQLE-dependent cholesterol biosynthesis via the AKT/mTOR signaling pathway. Additionally, as an RNA acetyltransferase, NAT10 enhances the stability of SQLE mRNA through ac4C modification, thereby revealing its dual synergistic role in promoting hepatocellular carcinogenesis. Both in vitro and in vivo experiments confirmed that inhibition of NAT10 reduces cellular cholesterol levels and suppresses tumorigenesis. Notably, the NAT10 inhibitor remodelin effectively curtailed HCC progression. Our findings identify NAT10 as a key metabolic regulator in HCC and propose targeting the NAT10-SQLE-cholesterol axis as a promising therapeutic strategy.