[Background] Abnormal lipid metabolism is an important metabolic event in the development of liver cancer. Role of lactic acid bacteria in regulating glucose and lipid metabolism has been widely reported. [Objective] To investigate whether Lactobacillus plantarum CGMCC8198 could regulate the HMGCR/SMYD3 lipid metabolism pathway, thereby affecting the occurrence and development of liver cancer cells. [Methods] HepG2 cells were treated with different concentrations (5, 10, 15 μg/mL) of Lactobacillus plantarum CGMCC8198 crushed supernatant (LpS) for different times. Western Blot, oil red staining and real-time quantitative PCR (RT-qPCR) were used to detect the effects of LpS on fatty degeneration of liver cancer cells and the key pathway of HMGCR/SMYD3 lipid metabolism; MTT, cell scratch test and flow cytometry were used to detect the effect of LpS on the proliferation, migration and apoptosis of HepG2 cells in the process of lipid metabolism disorders. [Results] The expression of key lipid metabolism genes such as HMGCR, SMYD3, SREBP-2 could be inhibited by LpS in lipid metabolism disorders liver cancer cells, while the proliferation and migration could be inhibited and the cell apoptosis could be promoted of liver cells in the process of lipid metabolism disorders. [Conclusion] LpS could inhibit the lipid metabolism of liver cancer cells by inhibiting the expression of key transcriptional regulators of lipid metabolism SREBP-2 and HMGCR, thereby promoting endogenous apoptosis of liver cancer cells.