LOX inhibition creates vulnerability to ferroptosis by decoupling glucose metabolism and mitophagy in triple-negative breast cancer

ABSTRACT: High degree of metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to its aggressiveness and resistance to standard therapies, necessitating identification of novel therapeutic vulnerabilities. Here, we identify non-canonical functions of an ECM remodeler protein, 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 interacts with and sequesters PARKIN, protecting HIF-1α from proteasomal degradation to increase transcription of glycolytic genes. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and triggers mitochondria-ER contacts (MERCs) via interacting with tethering factors, e.g., HSP90, leading to mitochondrial fusion, increased membrane potential, and OXPHOS. While inhibiting LOX disrupts mitochondrial dynamics and reduces anti-oxidant defense elements GPX4 and FSP1, it triggers compensatory DHODH activity. Our one-two punch approach by targeting LOX in combination with the clinical DHODH inhibitor, leflunomide mediates tumor regression in a chemo-free setting in highly aggressive, chemoresistant PDX models without toxicity. Notably, LOX protein expression correlates with GPX4 in TNBC patient tumors. Together, these findings reveal LOX as a therapeutic target to induce vulnerability to DHODH inhibition-mediated ferroptosis in TNBC.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Jennifer Bethard  

LAB HEAD: Ozgur Sahin

PROVIDER: PXD071741 | Pride | 2026-07-06

REPOSITORIES: Pride