METTL1-mediated m7G modification of ASNS mRNA regulates asparagine metabolism reprogramming to promote hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy, notorious for its high recurrence, substantial drug resistance, and poor prognosis. Although METTL1, a key regulator of RNA m7G modification, is implicated in the progression of various cancers, its role and underlying mechanisms in HCC remain poorly understood. This study identified that METTL1 was significantly upregulated in HCC tissues, correlating with advanced stages and poor survival. Knockdown of METTL1 inhibited cell proliferation, migration, and invasion, which was reversed by restoring METTL1 expression. Multi-omics analysis indicated that METTL1 regulated gene expression through m7G modification, particularly in the Wnt, mTOR signaling pathways, and amino acid metabolism (especially asparagine metabolism). Further analysis revealed that METTL1 increased the stability and upregulated the expression levels of asparagine synthetase (ASNS) mRNA through m7G modification, thereby reprogramming asparagine metabolism and activating the mTOR pathway, ultimately promoting HCC progression. In conclusion, METTL1 regulated ASNS mRNA stability and expression via m7G modification, driving HCC malignancy through reprogramming of asparagine metabolism and activation of the mTOR signaling pathway.