{"doi":"10.1002/advs.202500221","title":"Nrf2 Drives Epigenetic Reprogramming and Acts as the Master Regulator of KLF4 Expression and Activity in Arsenic‐Induced Transformation","abstract":"Emerging evidence suggests that Nrf2 plays a pro-carcinogenic role in multiple cancers. Previous studies have shown that arsenic-induced Nrf2 activation drives metabolic reprogramming, leading to the formation of cancer stem-like cells. Here, we further demonstrate that KLF4, a key pluripotency factor, is a direct transcriptional target of Nrf2 in arsenic-treated human bronchial epithelial cells (BEAS-2B). Global chromatin immunoprecipitation sequencing (ChIP-seq) revealed multiple Nrf2 binding peaks within the KLF4 locus, overlapping with the enhancer markers H3K4me1 and H3K27Ac. Nrf2 knockout diminished KLF4 expression and reduced enhancer marker enrichment, accompanied by a global decrease in KLF4 genomic occupancy in BEAS-2B cells. Additionally, arsenic exposure enhances KLF4 binding at genes implicated in oncogenic pathways, including STAT3, SOX2, Nrf2 itself, cell growth regulators, Hedgehog signaling components, and epithelial-to-mesenchymal transition (EMT) markers. Notably, we identified a self-reinforcing feedback loop between Nrf2 and KLF4 that amplifies their oncogenic effects. Finally, our data reveal that Nrf2-KLF4 co-occupancy is essential for establishing active enhancer hubs across the genome. Collectively, these findings suggest that Nrf2's oncogenic effects are, in part, mediated through the Nrf2-dependent amplification of KLF4 expression and function. Targeting both Nrf2 and KLF4 may, therefore, represent a promising therapeutic strategy to eliminate arsenic-induced cancer stem-like cells.","journal":"Advanced Science","year":2025,"id":8498,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0539,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-08-04","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":73948,"name":"Zhuoyue Bi","orcid":"0000-0001-8559-3543","position":1,"is_corresponding":false},{"id":73949,"name":"Jessica Bamrah","orcid":null,"position":2,"is_corresponding":false},{"id":73950,"name":"Yiran Qiu","orcid":"0000-0001-8669-1209","position":3,"is_corresponding":false},{"id":73951,"name":"Wenxuan Zhang","orcid":"0000-0002-2046-3366","position":4,"is_corresponding":false},{"id":73952,"name":"Bandar Saeed Almutairy","orcid":null,"position":5,"is_corresponding":false},{"id":73953,"name":"Haoyan Ji","orcid":"0000-0002-3456-6083","position":6,"is_corresponding":false},{"id":73954,"name":"John D. Haley","orcid":"0000-0002-0283-6413","position":7,"is_corresponding":false},{"id":73955,"name":"Chitra Thakur","orcid":"0000-0002-4356-2543","position":8,"is_corresponding":false},{"id":24055,"name":"Fei Chen","orcid":"0000-0003-2308-3649","position":9,"is_corresponding":false},{"id":73956,"name":"Bandar Almutairy","orcid":null,"position":10,"is_corresponding":false},{"id":73947,"name":"Ziwei Wang","orcid":"0000-0002-8799-812X","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","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":[]}