Aligned with ferroptosis restricting circulating cancer cells, the BDH2–2,5-DHBA pathway protects mesenchymal cells from ferroptosis in the blood, boosting their capacity to seed secondary organs.

Restoring BDH2 or supplementing 2,5-DHBA rescues iron transfer, lysosomal pH, and ferroptosis resistance.

When BDH2 is lost, iron gets trapped in lysosomes, lysosomal pH rises, and contacts weaken. As a consequence, mesenchymal cells become highly vulnerable to ferroptosis.

We show that BDH2 is a key regulator of inter-organelle Fe(II) transfer. In melanocytic cells, BDH2 localizes at mitochondria–lysosome contacts. There it produces the siderophore 2,5-DHBA, which ferries Fe(II) into mitochondria. This supports respiration and lysosomal acidification.