Lysyl oxidase (LOX) inhibition creates vulnerability to ferroptosis by disrupting mitochondrial homeostasis in TNBC

Here, we identify previously unrecognized, non-canonical functions of ECM remodeler, lysyl oxidase (LOX), in coupling glucose metabolism with mitophagy and redox homeostasis, and show that inhibiting LOX generates a targetable vulnerability to ferroptosis, an iron-mediated cell death.

Mechanistically, LOX directly interacts with PARKIN and its upstream kinase PINK1, which we identified as a novel LOX substrate. LOX-mediated PINK1 oxidation prevents PARKIN phosphorylation, preventing HIF-1α proteasomal degradation, increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and triggers mitochondria-ER contacts via preventing VDAC1 proteasomal degradation, while the LOX-HSP90 complex promotes mitochondrial CA2+ transport.