PXD055896-1

PXD055896 is an original dataset announced via ProteomeXchange.

Title	NRF2 translation block by inhibition of cap-dependent initiation sensitizes lymphoma cells to ferroptosis and CAR-T immunotherapy
Description	Cancers coopt stress-response pathways to drive oncogenesis, dodge immune surveillance, and resist cytotoxic therapies. Several of these provide protection from ferroptosis, iron-mediated oxidative cell death. Here, we found dramatic sensitization to ferroptosis upon disruption of cap-dependent translation in diffuse large B-cell lymphoma (DLBCL). Specifically, rocaglate inhibitors of the eIF4A1 RNA helicase synergized with pharmacologic ferroptosis inducers, driven by a collapse of glutathione production that protects polyunsaturated fatty acids from ferroptotic oxidation. These effects occur despite initial up-regulation of specific protective factors. We find lost translation of NRF2, oncogenic master regulator of antioxidant gene-expression, is a key consequence of eIF4A1 inhibition. In vivo, combination of the clinical rocaglate zotatifin with a pharmacologically optimized ferroptosis inducer eradicated DLBCL patient derived xenografts. Moreover, we found zotatifin pre-exposure sensitized DLBCL to CD19-directed chimeric antigen receptor (CAR-19) T cells. Translational disruption therefore provides new opportunities to leverage therapeutic impacts of ferroptosis inducers including cytotoxic immunotherapies.
HostingRepository	PRIDE
AnnounceDate	2025-04-03
AnnouncementXML	Submission_2025-04-03_07:53:39.743.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD055896
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Kyle Hoffman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-16 06:17:23	ID requested
⏵ 1	2025-04-03 07:53:40	announced

10.6019/PXD055896;

submitter keyword: rocaglate inhibitors,ferroptosis, cap-dependent translation

Jonathan H. Schatz
contact affiliation	Sylvester Comprehensive Cancer Center, Miami, FL, US. Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida, US.
contact email	jschatz@med.miami.edu
lab head
Kyle Hoffman
contact affiliation	Bioinformatics Solutions Inc.
contact email	khoffman@bioinfor.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055896
     1. Label: PRIDE project
     2. Name: NRF2 translation block by inhibition of cap-dependent initiation sensitizes lymphoma cells to ferroptosis and CAR-T immunotherapy