{"doi":"10.1101/2025.09.02.673601","title":"Leveraging BRG1 Driven Ferroptosis Resistance to Overcome Treatment Resistance","abstract":"Resistance to Bruton's tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies, limiting treatment durability. Here, we identify ferroptosis suppression as a central mechanism of BTKi resistance in mantle cell lymphoma (MCL). Aberrant BRG1 activity protects cells from BTKi-induced ferroptosis by restricting reactive oxygen species (ROS) and labile iron. Mechanistically, BRG1 promotes resistance through both BTK-dependent survival signaling and a BTK-independent transcriptional program. The latter is mediated by BRG1-driven induction of MEF2B, which upregulates NDUFA4L2 to inhibit mitochondrial respiration, thereby blocking mitochondria-dependent ferroptosis. Pharmacologic inhibition of BRG1 disrupts these programs, restoring ferroptotic sensitivity and synergizing with BTKi across resistant MCL models. Together, these findings establish BRG1 as a central regulator of therapy resistance and provide a rationale for co-targeting BRG1 and BTK as a therapeutic strategy for B-cell malignancies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":574259,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1482051,"name":"Helgi Nikolli","orcid":null,"position":1,"is_corresponding":false},{"id":438213,"name":"Belem Yoval‐Sánchez","orcid":"0000-0002-7276-278X","position":2,"is_corresponding":false},{"id":1482052,"name":"Sieun Yang","orcid":null,"position":3,"is_corresponding":false},{"id":995698,"name":"Peter Martin","orcid":"0000-0002-1214-5149","position":4,"is_corresponding":false},{"id":357155,"name":"Caitlin Gribbin","orcid":null,"position":5,"is_corresponding":false},{"id":572553,"name":"Lalit Sehgal","orcid":"0000-0002-1151-5427","position":6,"is_corresponding":false},{"id":410149,"name":"Lapo Alinari","orcid":"0000-0002-8870-4162","position":7,"is_corresponding":false},{"id":308656,"name":"Robert A. Baiocchi","orcid":"0000-0002-1619-4853","position":8,"is_corresponding":false},{"id":457433,"name":"Inah Hwang","orcid":"0000-0002-4479-9374","position":9,"is_corresponding":false},{"id":384078,"name":"Xiangao Huang","orcid":null,"position":10,"is_corresponding":false},{"id":1482053,"name":"Maurizio DiLiberto","orcid":null,"position":11,"is_corresponding":false},{"id":240932,"name":"Alexander Galkin","orcid":"0000-0001-8469-2283","position":12,"is_corresponding":false},{"id":315434,"name":"Hojoong Kwak","orcid":"0000-0003-3932-8946","position":13,"is_corresponding":false},{"id":382673,"name":"Selina Chen‐Kiang","orcid":"0000-0002-8549-6177","position":14,"is_corresponding":false},{"id":281249,"name":"Hongwu Zheng","orcid":"0000-0002-5823-4913","position":15,"is_corresponding":false},{"id":457434,"name":"Jihye Paik","orcid":"0000-0002-5481-2202","position":16,"is_corresponding":false},{"id":1481692,"name":"Soo‐Yeon Hwang","orcid":"0000-0002-8548-5777","position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T02:57:40.686992Z","pmid":"40950195","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}