Objective To study the effect of DNA methyltransferase 1 (DNMT1) on sm-like protein-4 (LSM4) in hepatocyte apoptosis in mice induced with Hcy. Methods 12 ApoE^-/- mice were divided into two groups: normal diet (ND, n=6) and high methionine diet (HMD, n=6) groups. Normal hepatocytes of NCTC1469 were divided into a normal group (control, 0 μL/L Hcy), Hcy intervention group (Hcy, 100 μL/L Hcy), NC siRNA-transfected control group (si NC group, 0 μmol/L Hcy), LSM4 siRNA-transfected group (si-LSM4 group, 0 μmol/L Hcy), DNMT1 siRNA transfected group (si-DNMT1 group, 0 μmol/L Hcy), NC siRNA-transfected Hcy intervention group (Hcy+si-NC group, 100 μmol/L Hcy), LSM4 siRNA-transfected Hcy intervention group (Hcy+si-LSM4 group, 100 μmol/L Hcy), and DNMT1 siRNA-transfected Hcy intervention group (Hcy+si-DNMT1 group, 100 μmol/L Hcy). Analysis of the expression of LSM4 in various tissues was conducted using the NCBI database. Quantitative real-time PCR (qRT-PCR) and Western blot were used to detect differences in LSM4 protein expression in mouse tissues (HMD and ND) and hepatocytes (control and Hcy). Western blot was used to detect the expression of Bcl2-associated X (Bax) and B-cell lymphoma-2 (Bcl-2). The cell apoptosis rate in the Control, Hcy, Hcy+si-NC, and Hcy+si-LSM4 groups were detected by flow cytometry. MethPrimer online software was used to analyze the CpG islands of LSM4 promoter region. The expression of LSM4 in the Hcy+si-DNMT1 group was detected by qRT-PCR and Western blot. Results The expression of LSM4 in HMD,Hcy group was higher than that in the ND and Control group (P<0.05). Bax protein expression was significantly higher, but Bcl-2 was significantly lower in Hcy group compared with those of the Control group (P<0.05). The expression of Bax protein was significantly lower, but the level of Bcl-2 was significantly higher in the Hcy+si-LSM4 group compared with those in the Hcy+si-NC group (P<0.05). The cell apoptosis rate in the Hcy group was higher than that in the Control group (P<0.05), while the apoptosis rate in the Hcy+si-LSM4 group was lower than that in the Hcy+si-NC group (P<0.05). MethPrimer database analysis showed that the promoter region of LSM4 was GC-rich, and there was one CpG island. Compared with the Hcy + si-NC group, the Hcy+si-DNMT1 group’s expression of LSM4 protein was increased (P<0.05). Conclusions DNMT1 regulates LSM4 hypomethylation to increase its expression, thereby promoting Hcy-induced apoptosis of mouse hepatocytes.