TP53, encoding a wellknown tumor suppressor p53, plays essential roles in tumor initiation and progression, and is frequently mutated in lung cancer.However, pharmacological stabilization and reactivation of p53have not been actively explored for targeted cancer therapies.Here, we identified a novel Cyclophilin A (CypA)small molecule inhibitor (HL001) that induces nonsmall cell lung cancer (NSCLC) cell cycle arrest and apoptosis via restoring p53 expression, and further stabilizes p53 through inhibiting the MDM2mediated p53 ubiqutination.The downregulation of G3BP1 by HL001 also contributes to p53 stabilization by inhibiting p53 redistribution from nucleus to cytoplasm.Furthermore, HL001 selectively suppresses tumor growth in p53 wildtype NSCLC harboring Arg72 homozygous alleles (p5372R) through disrupting interaction between MDM2 and p5372R in a CypAdependent manner.Finally, administration of HL001 alone or cotreatment with cisplatin promotes significant tumor suppression in orthotopic NSCLC mouse model Collectively, our preclinical study demonstrated that HL001, a small molecule inhibitor of CypA, selectively activated p53WT 72R homozygote and thus inhibits growth of human lung cancer cells.The results presented here demonstrate that the utility of CypA inhibitors serve as an approach to the targeted therapy for individual lung cancer patient.