{"doi":"10.1016/j.redox.2023.102650","title":"Redox phospholipidomics discovers pro-ferroptotic death signals in A375 melanoma cells in vitro and in vivo","abstract":"Growing cancer cells effectively evade most programs of regulated cell death, particularly apoptosis. This necessitates a search for alternative therapeutic modalities to cause cancer cell's demise, among them - ferroptosis. One of the obstacles to using pro-ferroptotic agents to treat cancer is the lack of adequate biomarkers of ferroptosis. Ferroptosis is accompanied by peroxidation of polyunsaturated species of phosphatidylethanolamine (PE) to hydroperoxy- (-OOH) derivatives, which act as death signals. We demonstrate that RSL3-induced death of A375 melanoma cells in vitro was fully preventable by ferrostatin-1, suggesting their high susceptibility to ferroptosis. Treatment of A375 cells with RSL3 caused a significant accumulation of PE-(18:0/20:4-OOH) and PE-(18:0/22:4-OOH), the biomarkers of ferroptosis, as well as oxidatively truncated products - PE-(18:0/hydroxy-8-oxo-oct-6-enoic acid (HOOA) and PC-(18:0/HOOA). A significant suppressive effect of RSL3 on melanoma growth was observed in vivo (utilizing a xenograft model of inoculation of GFP-labeled A375 cells into immune-deficient athymic nude mice). Redox phospholipidomics revealed elevated levels of 18:0/20:4-OOH in RSL3-treated group vs controls. In addition, PE-(18:0/20:4-OOH) species were identified as major contributors to the separation of control and RSL3-treated groups, with the highest variable importance in projection predictive score. Pearson correlation analysis revealed an association between tumor weight and contents of PE-(18:0/20:4-OOH) (r = -0.505), PE-18:0/HOOA (r = -0.547) and PE 16:0-HOOA (r = -0.503). Thus, LC-MS/MS based redox lipidomics is a sensitive and precise approach for the detection and characterization of phospholipid biomarkers of ferroptosis induced in cancer cells by radio- and chemotherapy.","journal":"Redox Biology","year":2023,"id":320194,"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":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9583,"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":110046,"name":"Alexandr A. Kapralov","orcid":"0000-0002-3006-916X","position":1,"is_corresponding":false},{"id":110056,"name":"Vladimir A. Tyurin","orcid":"0000-0002-3474-1697","position":2,"is_corresponding":false},{"id":110060,"name":"Galina V. Shurin","orcid":"0000-0002-4864-0467","position":3,"is_corresponding":false},{"id":235148,"name":"Andrew A. Amoscato","orcid":"0000-0002-1340-9150","position":4,"is_corresponding":false},{"id":320291,"name":"Dhivyaa Rajasundaram","orcid":"0000-0001-7417-8002","position":5,"is_corresponding":false},{"id":234919,"name":"Hua Tian","orcid":"0000-0002-3598-0219","position":6,"is_corresponding":false},{"id":628965,"name":"Yuri L. Bunimovich","orcid":"0000-0002-7920-8781","position":7,"is_corresponding":false},{"id":245075,"name":"Yulia Nefedova","orcid":"0000-0002-5121-9294","position":8,"is_corresponding":false},{"id":553782,"name":"William G. Herrick","orcid":"0000-0003-1570-3641","position":9,"is_corresponding":false},{"id":403214,"name":"Ralph E. Parchment","orcid":null,"position":10,"is_corresponding":false},{"id":30164,"name":"James H. Doroshow","orcid":"0000-0002-4463-1790","position":11,"is_corresponding":false},{"id":110070,"name":"Hülya Bayır","orcid":"0000-0003-2361-4120","position":12,"is_corresponding":false},{"id":553781,"name":"Apurva K. Srivastava","orcid":"0000-0002-6390-7553","position":13,"is_corresponding":false},{"id":110071,"name":"Valerian E. Kagan","orcid":"0000-0002-7245-1885","position":14,"is_corresponding":false},{"id":110049,"name":"Yulia Y. Tyurina","orcid":"0000-0003-0287-2091","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:07:22.377587Z","pmid":"36870109","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":[]}