{"doi":"10.1172/jci166647","title":"RB1-deficient prostate tumor growth and metastasis are vulnerable to ferroptosis induction via the E2F/ACSL4 axis","abstract":"Inactivation of the RB1 tumor suppressor gene is common in several types of therapy-resistant cancers, including metastatic castration-resistant prostate cancer, and predicts poor clinical outcomes. Effective therapeutic strategies against RB1-deficient cancers remain elusive. Here, we showed that RB1 loss/E2F activation sensitized cancer cells to ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, by upregulating expression of ACSL4 and enriching ACSL4-dependent arachidonic acid-containing phospholipids, which are key components of ferroptosis execution. ACSL4 appeared to be a direct E2F target gene and was critical to RB1 loss-induced sensitization to ferroptosis. Importantly, using cell line-derived xenografts and genetically engineered tumor models, we demonstrated that induction of ferroptosis in vivo by JKE-1674, a highly selective and stable GPX4 inhibitor, blocked RB1-deficient prostate tumor growth and metastasis and led to improved survival of the mice. Thus, our findings uncover an RB/E2F/ACSL4 molecular axis that governs ferroptosis and also suggest a promising approach for the treatment of RB1-deficient malignancies.","journal":"Journal of Clinical Investigation","year":2023,"id":316353,"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":106,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1019820,"name":"Jiaqi Chen","orcid":"0009-0009-9747-1610","position":1,"is_corresponding":false},{"id":449411,"name":"Yi Lu","orcid":"0000-0003-1221-6709","position":2,"is_corresponding":false},{"id":1020535,"name":"Alyssa Bawcom","orcid":null,"position":3,"is_corresponding":false},{"id":1019821,"name":"Jinjin Wu","orcid":"0000-0003-0643-0899","position":4,"is_corresponding":false},{"id":246226,"name":"Jianhong Ou","orcid":"0000-0002-8652-2488","position":5,"is_corresponding":false},{"id":3257,"name":"John M. Asara","orcid":"0000-0001-7450-2589","position":6,"is_corresponding":false},{"id":260281,"name":"Andrew J. Armstrong","orcid":"0000-0001-7012-1754","position":7,"is_corresponding":false},{"id":291660,"name":"Qianben Wang","orcid":"0000-0003-2636-7145","position":8,"is_corresponding":false},{"id":284391,"name":"Lei Li","orcid":"0000-0002-8828-5199","position":9,"is_corresponding":false},{"id":228079,"name":"Yuzhuo Wang","orcid":"0000-0002-9749-8591","position":10,"is_corresponding":false},{"id":290797,"name":"Jiaoti Huang","orcid":"0000-0003-1195-1998","position":11,"is_corresponding":false},{"id":566052,"name":"Ming Chen","orcid":"0000-0001-5041-9342","position":12,"is_corresponding":false},{"id":1019819,"name":"Mu‐En Wang","orcid":"0000-0002-5953-3499","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T01:06:38.213358Z","pmid":"36928314","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":[]}