• DNMT1-mediated hypermethylation of PTEN, H19, and RCAN1.4 promotes HSC activation. • DNMT3a-mediated DNA methylation of PTGIS and Septin9 promotes HSC activation. • DNMT3b-mediated hypermethylation of SUN2 promotes HSC activation. • Increased expression of MAT2A and MAT2β results in global DNA hypomethylation and promotes HSC activation. • NNMT induced by HSCs activation promotes HCC metastasis. Here, PTGIS is linked to hepatocellular carcinoma.