Albendazole induces ferroptosis through the USP7-GPX4 axis in B-cell acute lymphoblastic leukemia

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological malignancy that still requires the development of novel therapeutic strategies. Here, leveraging a drug-repurposing strategy, we performed a high-throughput screen of 3008 U.S. Food and Drug Administration (FDA)-approved drugs and identified albendazole (ABZ), a benzimidazole anthelmintic, as a potent agent against B-ALL across multiple preclinical models. Mechanistically, ABZ directly binds ubiquitin-specific protease 7 (USP7) and triggers its autophagy-dependent destabilization, subsequently promoting the ubiquitin-proteasome-mediated degradation of glutathione peroxidase 4 (GPX4), thereby inducing ferroptosis in B-ALL. Our study revealed that USP7 directly interacts with and stabilizes GPX4 by removing K48-linked ubiquitin chains, and both proteins are markedly upregulated in B-ALL patients, correlating with poor survival. Collectively, we identify a previously unrecognized USP7-GPX4 axis that governs ferroptosis and show that ABZ, as a novel ferroptosis inducer, triggers ferroptosis by targeting this axis, supporting clinical repurposing of albendazole or therapeutic targeting of USP7-GPX4 to improve B-ALL outcomes.