Metformin dual-targets metabolism and survival pathways in BPDCN.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with limited therapeutic options. Metformin, a commonly prescribed antidiabetic drug, has recently gained attention for its anticancer potential, but its effects on BPDCN remain unknown. Here, we show that metformin reduces cell viability and induces caspase-dependent apoptosis in both established (CAL-1, GEN2.2) and primary BPDCN cells, partly through activation of the intrinsic apoptotic pathway. Mechanistically, metformin activates AMPK and disrupts mitochondrial respiration and glycolysis, while inhibiting key oncogenic signaling pathways including Akt/mTOR, NF-κB, STAT3, and STAT5. In vivo, metformin reduces tumor cell infiltration in the spleen and modulates NF-κB and STAT5 signaling, although its effect on overall disease progression is limited. These results identify metformin as a multifaceted agent targeting both metabolic and survival pathways in BPDCN, supporting its potential as a therapeutic strategy in this rare malignancy.