PXD071741-1

PXD071741 is an original dataset announced via ProteomeXchange.

Title	LOX inhibition creates vulnerability to ferroptosis by decoupling glucose metabolism and mitophagy in triple-negative breast cancer
Description	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.
HostingRepository	PRIDE
AnnounceDate	2026-07-06
AnnouncementXML	Submission_2026-07-06_07:16:37.905.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jennifer Bethard
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-08 19:19:06	ID requested
⏵ 1	2026-07-06 07:16:38	announced

Dataset with its publication pending

submitter keyword: mitophagy, TNBC, ER-mitochondria contacts (MERCS), DHODH, ferroptosis,Lysyl oxidase (LOX), glucose metabolism

Ozgur Sahin
contact affiliation	Professor and SmartState Endowed Chair Department of Biochemistry and Molecular Biology Hollings Cancer Center Medical University of South Carolina
contact email	sahin@musc.edu
lab head
Jennifer Bethard
contact affiliation	Medical University of SC
contact email	bethard@musc.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/07/PXD071741

PRIDE project URI

• PRIDE
  1. PXD071741
     1. Label: PRIDE project
     2. Name: LOX inhibition creates vulnerability to ferroptosis by decoupling glucose metabolism and mitophagy in triple-negative breast cancer