摘要The single-nucleotide polymorphism(SNP)of p53,in particular the codon 72 variants,has recently been implicated as a critical regulator in tumor progression.However,the underlying mechanism remains elusive.Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation.Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant(but not p5372R)with phosphoserine aminotransferase 1(PSAT1).Interestingly,p5372P-PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γ coactivator 1α(PGC-1α)that otherwise bound to p5 372P,leading to subsequent nuclear translocation of PGC-1α and activation of oxidative phosphorylation(OXPHOS)and tricarboxylic acid(TCA)cycle.Depletion of PSAT1 restored p5 3 72P-PGC-1αinteraction and impeded the OXPHOS and TCA function,resulting in mitochondrial dysfunction and metastasis suppression.Notably,pharmacological targeting the PSAT1-p5 3 72P interaction by aminooxyacetic acid(AOA)crippled the growth of liver cancer cells carrying the p5 3 72P variant in both in vitro and patient-derived xenograft models.Moreover,AOA plus regorafenib,an FDA-proved drug for hepatocellular carcinoma and colorectal cancer,achieved a better anti-tumor effect on tumors carrying the p5372P variant.Therefore,our findings identified a gain of function of the p5 372P variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p5372P-PSAT1 perturbation.