Gambogic acid restores wild-type-like p53 functions to induce ferroptosis in mutant p53 cancer cells

TP53, the most frequently mutated gene in human cancers, undergoes a functional transformation from a tumor suppressor to an oncoprotein, thereby enhancing tumor aggressiveness, metastatic potential, and resistance to therapy. Given the prevalence of p53 mutations in cancer, the reactivation of wild-type p53 function presents a compelling therapeutic strategy for these malignancies. In this study, we identified gambogic acid (GA), a natural compound, as a potent reactivator of mutant p53 transcriptional activity. Immunofluorescence and co-immunoprecipitation assays revealed that GA treatment upregulates wild-type p53 expression while depleting mutant p53 in cancer cells. The time-dependent restoration of p53′s DNA-binding capacity and transcriptional regulatory activity by GA was further demonstrated through EMSA and ChIP. Consequently, GA robustly induced the expression levels of canonical p53 downstream target genes, confirming functional restoration of p53 signaling. In addition, GA synergizes with RSL3, a GPX4 inhibitor, to promote ferroptosis in mutant p53 cancer cells in both cellular and animal studies. In summary, our findings identify GA as a promising compound that reactivates mutant p53 through thiol modification, restoring its wild-type function and inducing ferroptosis in p53-mutant cancer cells. The findings of this study establish a foundational rationale and new perspectives for a mutant p53-directed therapeutic paradigm in oncology.