Objective To study the effect of DNA methyltransferase 1 (DNMT1) on sm-like protein-4 (LSM4) in the hepatocytes apoptosis of mice induced by Hcy. Methods 12 ApoE-/- mice were divided into two groups: normal diet (ND, n = 6), high methionine diet (HMD, n = 6). Normal hepatocytes of NCTC1469 were divided into normal group (control, 0 μL/L Hcy), Hcy intervented group (Hcy, 100 μL/L Hcy), transfected NC siRNA control group (si-NC group, 0 μmol/L Hcy), transfected LSM4 siRNA group (si-LSM4 group, 0 μmol/L Hcy), transfected DNMT1 siRNA group (si-DNMT1 group, 0 μmol/L Hcy), transfected NC siRNA in the Hcy intervened group (Hcy＋si-NC group, 100 μmol/L Hcy), transfected LSM4 siRNA in the Hcy intervened group (Hcy＋si-LSM4 group, 100 μmol/L Hcy) and transfected siRNA DNMT1 in the Hcy intervened group (Hcy＋si-DNMT1 group, 100 μmol/L Hcy); Analysis of the expression of LSM4 in various tissues by NCBI database; quantitative real-time PCR (qRT-PCR) and Western blot (WB) were used to detect the difference of LSM4 protein expression in mice tissues (HMD and ND) and hepatocytes (control and Hcy). Western blot was used to detect the protein expression of Bcl2-associated X (Bax) and B-cell lymphoma-2 (Bcl-2). The cell apoptosis rate of control, Hcy, Hcy＋si-NC and Hcy＋si-LSM4 were detected by flow cytometry. MethPrimer online software was used to analyze the CpG islands of LSM4 promoter region. The expression of LSM4 in 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 control group (P＜0.05). Bax protein expression in Hcy＋si-LSM4 was significantly higher than that in the control group (P＜0.05), but Bcl-2 was significantly lower (P＜0.05). The expression of Bax in Hcy＋si-LSM4 was significantly lower than that in Hcy＋si-NC group (P＜0.05), and the level of Bcl-2 was significantly increased. The cell apoptosis rate in Hcy group was higher than that in the control group (P＜0.05). The cell apoptosis rate in 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 expression of LSM4 protein in the Hcy+si-DNMT1 group was increased (P＜0.05). Conclusions DNMT1 regulates LSM4 hypomethylation to increase its expression, thereby promoting Hcy-induced apoptosis of mouse hepatocytes.