Updated project metadata. Metabolic dysregulation is an important feature of malignant tumors. Serine synthesis pathway (SSP) reshapes tumor cells to enhance their growth and survival capabilities, especially under serine starvation. However, whether and how SSP is involved in the progression of liver cancer has not been clearly stated. We applied a combination of quantitative proteomics and transcriptomics and discovered the increased expression of PHGDH and PSAT1 in mice liver cancer induced by SB. PHGDH is the first rating-limited enzyme of SSP and the conditional knockout of PHGDH in liver impaired the advanced liver cancer formation. However, the specific inhibition of enzymatic activity of PHGDH in liver has no obvious suppressive effect on advanced liver cancer. Further, we explored a non-metabolic function of PHGDH, which used its ACT domain to bind and regulate cMyc transcriptional activity, then selectively activated genes expression of Lcn2, Got1, Fabp5 and Psat1, indicating PHGDH drives/links multiple metabolic pathways and augmented its function through its non-metabolic role. In addition, the mutant p53 would release the suppression of PHGDH in mice liver cancer model and clinical liver cancer samples. Hence, the mutant p53/PHGDH/cMyc axis could be a potential target to cure advanced liver cancer.