Mebendazole induces ZBP-1 mediated PANoptosis of acute myeloid leukemia cells by targeting TUBA1A and exerts antileukemia effect

Despite notable advancements in AML therapy in recent years, a substantial proportion of patients remain refractory or at high risk of recurrence with limited efficacy. Therefore, it's urgent to develop novel drugs for treating AML. The small molecule drug library was utilized to screen for drugs that elicit the inflammatory death of AML cells. Cell viability, cell morphological analysis, western blotting, and RNA-seq were used to determine the pathway of Mebendazole (MBD)-induced AML cell death. Cell cycle analysis, protein expression profiling, molecular docking, western blotting and lentivirus overexpression were used to analyze the target protein of MBD in AML cells. The anti-AML activity of MBD in vivo was evaluated using tumor xenograft models constructed by AML cell lines and patient-derived primary AML cells. In this study, we have identified Mebendazole (MBD), a conventional anthelmintic drug known for its low toxicity and cost, as a potent agent that exerts significant anti-AML effects in vitro. Furthermore, we have observed its inhibitory effects on the invasion of AML cell lines and primary AML cells in xenograft mouse models, while noting its negligible toxic side effects in normal mice in vivo. Mechanically, MBD inhibits the cell cycle in G2/M phase by inhibiting tubulin α1A (TUBA1A) and promotes ZBP-1 mediated PANoptosis in AML cells. Our results confirm that MBD exerts anti-AML activity in preclinical models. These results highlight the remarkable clinical translational potential of MBD, providing new potential medicine for AML patients. In addition, TUBA1A can be used potential novel therapeutic target in tumors with abnormal TUBA1A expression.