These findings highlight the dual role of STAT3 as both a transcriptional repressor of p53 and an indirect facilitator of p53 turnover, positioning STAT3 inhibition as a powerful strategy to reinstate p53-dependent tumor-suppressive responses; our combined targeting of MDM2 and STAT3 with RG7388 and BBI608 synergistically enhanced p53 stabilization and downstream apoptosis in leukemia cell lines, validating this dual-target approach. Here, TP53 is linked to leukemia.