GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE338nnn/GSE338674/primaryOK200OtherHomo sapiensOtherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE338674GEOGSEfalseLysyl oxidase (LOX) inhibition creates vulnerability to ferroptosis by disrupting mitochondrial homeostasis in TNBCHigh degree of metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contributes to its aggressiveness and resistance to standard therapies, necessitating identification of novel therapeutic vulnerabilities. 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. Inhibiting LOX disrupts mitochondrial dynamics, reduces OXPHOS and antioxidant GPX4/FSP1, while triggering compensatory DHODH activity in a mitophagy-dependent manner. Our ‘one-two punch’ approach combining LOX inhibitor or shLOX with clinical DHODH inhibitor, leflunomide, leads to strong tumor growth inhibition in multiple in vivo models in a chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in patient tumors. Together, we present LOX as a therapeutic target, inducing vulnerability to ferroptosis in TNBC.2026/07/19GSE338674GSM9879517GSM9879516GSM9879513GSM9879512GSM9879515GSM9879514GSM9879511GSM987951024676338674Homo sapiens