Repurposed fludarabine alleviates type 1 diabetes through the dual effects on dendritic cell activation and β cell ferroptosis

Type 1 diabetes (T1D) imposes a substantial burden on patients yet effective therapies to halt disease progression are lacking. Immunomodulatory strategies that suppress autoreactive immune response and preserve pancreatic β cell function are essential for improving long-term therapeutic outcome. Herein, we repurposed fludarabine, a clinically applied drug, in the T1D setting. Fludarabine treatment markedly alleviates inflammatory immune activation and β cell destruction. Moreover, fludarabine induces tolerogenic dendritic cell (DC) phenotype through chemical reprogramming. The protective effect of fludarabine-treated DCs was further corroborated by adoptive transfer experiment. Mechanistically, fludarabine directly binds to STAT1 and disrupts its interaction with the aryl hydrocarbon receptor (AHR), thereby facilitating AHR nuclear translocation. Activated AHR transcriptionally upregulates anti-inflammatory and anti-ferroptotic programs, conferring a tolerogenic DC phenotype and protecting β cells from stress-induced ferroptosis. Collectively, our findings identify fludarabine as a promising immunometabolic therapeutic candidate that restores immune tolerance and enhances β cell resilience, which could be a viable approach against T1D in clinical settings.