Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC
Year: 2026
Type: article
Abstract: High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca 2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.
Source: Cell Reports Medicine
Authors: Ozge Saatci, Burge Ulukan, Metin Cetin, Hellen Kuasne, Constanza Martinez, Elif Percin, Natalia Oleinik, Matthew T. Savoca, Ali Nehme, Aldo Hernández-Corchado, Evelyn Zavacky, Kukkamudi Sreenivas, Abdol H. Rezaeian, Jennifer R. Bethard, Jean-Sebastien Anoma, Ozlem Sener Sahin, Ozlem Sener Sahin, Adriana Aguilar-Mahecha, Marguerite Buchanan, Mertkaya Aras, Genevieve DeBlois, Mark Basik, Elizabeth G. Hill, Lauren E. Ball, Chintada Nageswara Rao, Campbell McInnes, Yasser Riazalhosseini, Hamed S. Najafabadi, John J. Lemasters, Besim Ogretmen, Morag Park, Ozgur Sahin, Ozgur Sahin
Institutions: Medical University of South Carolina, MUSC Hollings Cancer Center, Institut du cancer Rosalind & Morris Goodman, McGill University, McGill University Health Centre, University of South Carolina, Jewish General Hospital, Lady Davis Institute for Medical Research, Institute for Research in Immunology and Cancer, Université de Montréal
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: EXTRAMURAL RESEARCH FACILITIEIS CONSTRUCTION, Quadrupole Orbitrap Hybrid Mass Spectrometer for Proteomics, G20728709, G2775861764, G3587049998, Confocal/Multiphoton Microscope Upgrade, G3715936215, G4263293667, G5239612601, G7848942919, South Carolina COBRE in Oxidants, Redox Balance and Stress Signaling, G841752465, Ceramide Signaling in the Regulation of Head & Neck Cancer Cell Death and Therapy, Overcoming chemoresistance in triple negative breast cancer, Inhibiting tumor growth and metastasis in highly aggressive breast cancers with centrosome amplification, Medical University of South Carolina - Cancer Center Support Grant
OpenAlex ID: W7168935371