{"doi":"10.1038/s41598-024-75786-3","title":"Non-electrophilic NRF2 activators promote wound healing in human keratinocytes and diabetic mice and demonstrate selective downstream gene targeting","abstract":"The transcription factor NRF2 plays an important role in many biological processes and is a promising therapeutic target for many disease states. NRF2 is highly expressed in the skin and is known to play a critical role in diabetic wound healing, a serious disease process for which treatment options are limited. However, many existing NRF2 activators display off-target effects due to their electrophilic mechanism, underscoring the need for alternative approaches. In this work, we investigated two recently described non-electrophilic NRF2 activators, ADJ-310 and PRL-295, and demonstrated their efficacy in vitro and in vivo in human keratinocytes and Lepr db/db diabetic mice. We also compared the downstream targets of PRL-295 to those of the widely used electrophilic NRF2 activator CDDO-Me by RNA sequencing. Both ADJ-310 and PRL-295 maintained human keratinocyte cell viability at increasing concentrations and maintained or improved cell proliferation over time. Both compounds also increased cell migration, improving in vitro wound closure. ADJ-310 and PRL-295 enhanced the oxidative stress response in vitro, and RNA-sequencing data showed that PRL-295 activated NRF2 with a narrower transcriptomic effect than CDDO-Me. In vivo, both ADJ-310 and PRL-295 improved wound healing in Lepr db/db diabetic mice and upregulated known downstream NRF2 target genes in treated tissue. These results highlight the non-electrophilic compounds ADJ-310 and PRL-295 as effective, innovative tools for investigating the function of NRF2. These compounds directly address the need for alternative NRF2 activators and offer a new approach to studying the role of NRF2 in human disease and its potential as a therapeutic across multiple disease states.","journal":"Scientific Reports","year":2024,"id":429026,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":983111,"name":"Han Chen","orcid":"0000-0003-2530-4118","position":1,"is_corresponding":false},{"id":1051816,"name":"Lin Chen","orcid":"0000-0001-6997-395X","position":2,"is_corresponding":false},{"id":1231101,"name":"Brian P. David","orcid":"0000-0001-5328-5394","position":3,"is_corresponding":false},{"id":418624,"name":"Junhe Shi","orcid":"0000-0001-6392-7397","position":4,"is_corresponding":false},{"id":1217965,"name":"Angela Xu","orcid":"0000-0002-4583-950X","position":5,"is_corresponding":false},{"id":1231102,"name":"Kornelia J. Skowron","orcid":"0000-0002-0846-6134","position":6,"is_corresponding":false},{"id":1231103,"name":"T. Johnson","orcid":"0000-0002-1291-004X","position":7,"is_corresponding":false},{"id":1231662,"name":"Reginald A. Woods","orcid":null,"position":8,"is_corresponding":false},{"id":408231,"name":"Aparna Ankireddy","orcid":null,"position":9,"is_corresponding":false},{"id":407355,"name":"Sekhar P. Reddy","orcid":"0000-0001-5027-9175","position":10,"is_corresponding":false},{"id":208768,"name":"Terry W. Moore","orcid":"0000-0002-5410-306X","position":11,"is_corresponding":false},{"id":246413,"name":"Luisa A. DiPietro","orcid":"0000-0002-4842-1547","position":12,"is_corresponding":false},{"id":246411,"name":"May Barakat","orcid":"0000-0002-3132-461X","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T01:59:06.668462Z","pmid":"39448644","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":[]}