Abstract: Objective To investigate the effect of sericin on the proliferation of human gastric cancer MKN45 cells and explore the underlying molecular mechanism. Methods MKN45 cells were transfected by LC3 double fluorescent autophagic virus, and the positive cells screened by puromycin were divided into blank group, sericin group and sericin + 3-MA group. After incubation with sericin for 48 h, the cells were examined for proliferation, apoptosis and cell cycle using CCK-8 assay and flow cytometry. Cell autophagy was detected by transmission electron microscopy (TEM) and fluorescent inverted microscope, and the autophagy-related markers including LC3, p62 and Beclin proteins were detected with Western blotting. Nude mice bearing gastric cancer xenograft were treated with normal saline or sericin injections (n=5) and the changes in the tumor volume and weight were measured. Results Compared with the blank group, MKN45 cells with sericin treatment showed significantly inhibited proliferation both in vitro and in nude mice. Autophagosomes were observed in sericin-treated cells under TEM and fluorescent inverted microscope. Sericin treatment of the cells significantly increased the cell apoptosis (P< 0.01), caused obvious cell cycle arrest in G2/M phase (P<0.01), up-regulated the expressions of both LC3-2 and Beclin, and down-regulated the expression of p62. The autophagy inhibitor 3-MA obviously antagonized the effects of sericin on cell apoptosis, cell cycle and autophagic protein expressions. Conclusion Sericin can inhibit the proliferation of human gastric cancer MKN45 cells by regulating cell autophagy to serve as potential anti-tumor agent.