{"doi":"10.1016/j.redox.2025.103848","title":"The absence of Peroxiredoxin-1 in human pancreatic ductal adenocarcinoma (PDAC) markedly reduces cell survival and tumor growth when coupled with the inhibition of Ref-1 redox signaling","abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to therapy, surviving despite hypoxia, oxidative stress, and nutrient deprivation. Redox effector factor-1 (Ref-1) regulates several oncogenic transcription factors (TFs) and is controlled by peroxiredoxins (PRDX). We investigated how Ref-1 inhibition by APX2014, combined with PRDX expression, affects pancreatic cancer cells from multiple patient lines. Silencing or CRISPR/Cas9 knockout of PRDX1-but not PRDX2-6-sensitized PDAC cell lines to APX2014 both in vitro and in vivo without affecting Ref-1's DNA repair function of apurinic/apyrimidinic endonuclease. The combination of PRDX1 loss and APX2014 treatment increased apoptosis and decreased TF activity (NF-κB, HIF-1α) and their downstream targets, TNFAIP2, Survivin, and CA9. A 3D co-culture with PRDX1-null tumor spheroids and cancer-associated fibroblasts (CAFs) showed that (i) Ref-1 inhibition impaired PRDX1-null tumor growth, and (ii) PRDX1 loss reduced CAF viability, highlighting redox crosstalk within the tumor microenvironment (TME). In a PDAC xenograft model, PRDX1-knockout tumors treated with APX2014 had smaller volumes, lighter weights, lower Ref-1, and decreased Ki-67, with improved animal survival. Patient microarrays indicated increased Ref-1 and PRDX1 levels versus normal tissue, emphasizing their clinical relevance. Overall, these data identify PRDX1 as a key factor for PDAC's susceptibility to Ref-1 blockade, suggesting dual targeting could disrupt TME redox signaling, limit tumor progression, and improve APX therapy. These findings support dual targeting of Ref-1 and PRDX1 as a promising therapeutic approach in PDAC and other redox-driven cancers.","journal":"Redox Biology","year":2025,"id":526710,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9636,"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":412515,"name":"Randall Wireman","orcid":null,"position":1,"is_corresponding":false},{"id":1217786,"name":"Jacqueline Peil","orcid":null,"position":2,"is_corresponding":false},{"id":702405,"name":"Dana K. Mitchell","orcid":"0000-0002-1022-1072","position":3,"is_corresponding":false},{"id":426999,"name":"Elizabeth A. Sierra Potchanant","orcid":"0000-0003-0040-5916","position":4,"is_corresponding":false},{"id":973110,"name":"Ratan Kumar","orcid":"0000-0001-6015-5539","position":5,"is_corresponding":false},{"id":479022,"name":"Jonah Z. Vilseck","orcid":"0000-0001-7076-8996","position":6,"is_corresponding":false},{"id":703161,"name":"Sha Cao","orcid":"0000-0003-3033-9219","position":7,"is_corresponding":false},{"id":1402830,"name":"Sanya Haiaty","orcid":"0000-0002-1784-4926","position":8,"is_corresponding":false},{"id":468331,"name":"Millie M. Georgiadis","orcid":"0000-0003-2976-4576","position":9,"is_corresponding":false},{"id":267419,"name":"Melissa L. Fishel","orcid":"0000-0002-9436-6382","position":10,"is_corresponding":false},{"id":269873,"name":"Mark R. Kelley","orcid":"0000-0001-9472-1826","position":11,"is_corresponding":false},{"id":707250,"name":"Sonia Kiran","orcid":"0000-0002-1902-3451","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T02:50:34.851930Z","pmid":"40902319","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":[]}