{"doi":"10.1016/j.redox.2025.103773","title":"Genome-wide mapping of arsenic-activated Nrf2 reveals metabolic and epigenetic reprogramming in induced pluripotent stem cells","abstract":"Arsenic (As 3+ ) is a well-established environmental carcinogen known to induce malignant transformation and cancer stem-like cell (CSC) properties in somatic cells, with Nrf2 functioning as a central regulator. However, the impact of chronic As 3+ exposure on pluripotent stem cells, particularly through Nrf2-mediated epigenetic and metabolic reprogramming, remains largely unexplored. In this study, we chronically exposed human induced pluripotent stem cells (iPSCs, Nips-B2) to an environmentally relevant concentration of trivalent arsenic (0.25 μM, As 3+ ) for three months. The tumorigenic potential of exposed iPSCs was evaluated using anchorage-independent growth assays and xenograft models, while mechanistic insights were gained via chromatin immunoprecipitation sequencing (ChIP-seq) for Nrf2 and key histone modifications (H3K4me3, H3K9me3, H3K27me3, H3K36me3, and H4K20me3), alongside transcriptomic profiling by RNA sequencing (RNA-seq). Prolonged exposure markedly enhanced tumor sphere formation in vitro and accelerated tumor growth in vivo , indicating the acquisition of CSC-like traits. Integrated ChIP-seq and RNA-seq analyses revealed widespread Nrf2 chromatin binding and global epigenetic remodeling, characterized by increased levels of H3K27me3, H3K36me3, and H4K20me3, a modest rise in H3K9me3, and reduced H3K4me3. Notably, As 3+ exposure enhanced Nrf2 binding at loci regulating glycolysis, cholesterol biosynthesis, self-renewal, and oncogenesis. Functional analyses confirmed that transcriptional and metabolic changes were Nrf2-driven and closely linked to H3K36me3 and H3K27me3 dynamics. Collectively, our findings demonstrate that chronic As 3+ exposure reprograms iPSCs through Nrf2 activation and coordinated epigenetic remodeling, revealing a novel mechanism by which environmental carcinogens exploit stem cell plasticity to initiate CSC-like transformation. • Chronic arsenic exposure induces CSC-like transformation in human iPSCs. • Nrf2 activation drives metabolic and transcriptional reprogramming in iPSCs. • Arsenic alters histone marks, enhancing H3K27me3 and H3K36me3 deposition. • Upregulated genes are enriched in glycolysis, cholesterol biosynthesis, and stemness. • Nrf2 and histone remodeling coordinately regulate CSC-associated gene expression.","journal":"Redox Biology","year":2025,"id":524018,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"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":73948,"name":"Zhuoyue Bi","orcid":"0000-0001-8559-3543","position":1,"is_corresponding":false},{"id":301316,"name":"Lisa Polin","orcid":"0000-0002-9189-055X","position":2,"is_corresponding":false},{"id":1396887,"name":"Ziqi Liu","orcid":"0000-0002-0977-2141","position":3,"is_corresponding":false},{"id":73950,"name":"Yiran Qiu","orcid":"0000-0001-8669-1209","position":4,"is_corresponding":false},{"id":73951,"name":"Wenxuan Zhang","orcid":"0000-0002-2046-3366","position":5,"is_corresponding":false},{"id":1151234,"name":"Aashna S. Pawar","orcid":null,"position":6,"is_corresponding":false},{"id":73955,"name":"Chitra Thakur","orcid":"0000-0002-4356-2543","position":7,"is_corresponding":false},{"id":1129405,"name":"Masaharu Seno","orcid":"0000-0001-8547-6259","position":8,"is_corresponding":false},{"id":73947,"name":"Ziwei Wang","orcid":"0000-0002-8799-812X","position":9,"is_corresponding":false},{"id":1276606,"name":"Fei Chen","orcid":"0000-0003-3829-3016","position":10,"is_corresponding":false},{"id":665349,"name":"Akimasa Seno","orcid":"0000-0002-9664-9490","position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:50:07.396155Z","pmid":"40729963","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":[]}