Albendazole induces ferroptosis via the USP7-GPX4 axis and enhances CAR-T immunotherapy in B-cell acute lymphoblastic leukemia

B-cell acute lymphoblastic leukemia (B-ALL) is a hematological malignancy that remains a significant clinical challenge, highlighting the urgent need for novel therapeutic strategies. Here, we performed a high-throughput screen of compounds approved by the U.S. Food and Drug Administration (FDA) and identified albendazole (ABZ), a benzimidazole anthelmintic, as a potent anti-leukemic agent against B-ALL. ABZ demonstrated robust cytotoxicity in B-ALL cell lines and patient-derived samples while sparing normal hematopoietic cells, and significantly reduced leukemia burden and prolonged survival in both cell line-derived and patient-derived xenograft models. Mechanistically, ABZ induced ferroptosis, characterized by lipid peroxidation, glutathione depletion, and ROS accumulation. ABZ promoted the ubiquitin-proteasome-mediated degradation of glutathione peroxidase 4 (GPX4) through autophagy-dependent destabilization of the deubiquitinase ubiquitin-specific protease 7 (USP7). USP7 was shown to directly interact with and stabilize GPX4 by removing K48-linked ubiquitin chains, and both proteins were markedly overexpressed in B-ALL patient samples, correlating with poor survival. Notably, ABZ also downregulated PD-L1 expression in leukemia cells, enhancing the efficacy of CD19 chimeric antigen receptor T (CAR-T) cell therapy in vitro and in vivo. Our findings delineate a previously unrecognized USP7-GPX4 axis regulating ferroptosis and provide a rationale for clinical repurposing of ABZ, alone or in combination with immunotherapies, to improve outcomes in B-ALL.