{"doi":"10.1101/2022.08.31.506025","title":"NRF2 activation induces NADH-reductive stress providing a metabolic vulnerability in lung cancer","abstract":"Abstract Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers, however the role of this pathway in cancers with wildtype KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines—an effect that was completely rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD + -consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":297076,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":984562,"name":"Maolin Ge","orcid":"0000-0002-8803-1463","position":1,"is_corresponding":false},{"id":985053,"name":"Addriaan de Groot","orcid":null,"position":2,"is_corresponding":false},{"id":985054,"name":"Alexander Carlin","orcid":null,"position":3,"is_corresponding":false},{"id":985055,"name":"Magdy Gohar","orcid":null,"position":4,"is_corresponding":false},{"id":985056,"name":"Hannah Fischer","orcid":null,"position":5,"is_corresponding":false},{"id":634873,"name":"Lei Shi","orcid":"0000-0003-1149-0474","position":6,"is_corresponding":false},{"id":984563,"name":"Ting-Yu Wei","orcid":"0000-0002-3073-625X","position":7,"is_corresponding":false},{"id":429785,"name":"Charles H. Adelmann","orcid":"0000-0001-7823-4374","position":8,"is_corresponding":false},{"id":985057,"name":"Tristan Vornbäumen","orcid":null,"position":9,"is_corresponding":false},{"id":985058,"name":"Benedkit R. Dürr","orcid":null,"position":10,"is_corresponding":false},{"id":6641,"name":"Mariko Takahashi","orcid":"0000-0003-2465-7907","position":11,"is_corresponding":false},{"id":985059,"name":"Marianne Richter","orcid":null,"position":12,"is_corresponding":false},{"id":615853,"name":"Junbing Zhang","orcid":"0000-0001-7746-1145","position":13,"is_corresponding":false},{"id":657557,"name":"Tzu-Yi Yang","orcid":null,"position":14,"is_corresponding":false},{"id":984564,"name":"Vindhya Vijay","orcid":"0000-0002-7886-7443","position":15,"is_corresponding":false},{"id":75641,"name":"Makiko Hayashi","orcid":"0000-0002-9189-0058","position":16,"is_corresponding":false},{"id":985060,"name":"David E. Fischer","orcid":null,"position":17,"is_corresponding":false},{"id":37113,"name":"Aaron N. Hata","orcid":"0000-0002-6127-318X","position":18,"is_corresponding":false},{"id":985061,"name":"Thales Papaginanakopoulos","orcid":null,"position":19,"is_corresponding":false},{"id":23529,"name":"Raúl Mostoslavsky","orcid":"0000-0002-7740-5212","position":20,"is_corresponding":false},{"id":50927,"name":"Nabeel Bardeesy","orcid":"0000-0003-3867-0416","position":21,"is_corresponding":false},{"id":6646,"name":"Liron Bar-Peled","orcid":"0000-0003-2687-9546","position":22,"is_corresponding":false},{"id":984561,"name":"Tommy Weiss‐Sadan","orcid":"0000-0003-4119-2275","position":0,"is_corresponding":true}],"reference_count":96,"raw_metadata":null,"created_at":"2026-07-19T00:31:21.257700Z","pmid":null,"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":[]}