{"doi":"10.3389/fnagi.2021.673205","title":"Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue","abstract":"The Keap1-Nrf2 signaling axis is a validated and promising target for cellular defense and survival pathways. This minireview discusses the potential off-target effects and their impact on future drug development originating from Keap1-targeting small molecules that function as displacement activators of the redox-sensitive transcription factor Nrf2. We argue that small-molecule displacement activators, similarly to electrophiles, will release both Nrf2 and other Keap1 client proteins from the ubiquitin ligase complex. This non-specificity is likely unavoidable and may result in off-target effects during Nrf2 activation by targeting Keap1. The small molecule displacement activators may also target Kelch domains in proteins other than Keap1, causing additional off-target effects unless designed to ensure specificity for the Kelch domain only in Keap1. A potentially promising and alternative therapeutic approach to overcome this non-specificity emerging from targeting Keap1 is to inhibit the Nrf2 repressor Bach1 for constitutive activation of the Nrf2 pathway and bypass the Keap1-Nrf2 complex.","journal":"Frontiers in Aging Neuroscience","year":2021,"id":163531,"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":41,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":644382,"name":"Navneet Ammal Kaidery","orcid":"0000-0002-3226-2107","position":1,"is_corresponding":false},{"id":644381,"name":"Manuj Ahuja","orcid":"0000-0002-4846-8249","position":2,"is_corresponding":false},{"id":644385,"name":"А. А. Полозников","orcid":"0000-0003-1816-8699","position":3,"is_corresponding":false},{"id":564320,"name":"Sudarshana M. Sharma","orcid":"0000-0002-9745-0061","position":4,"is_corresponding":false},{"id":644386,"name":"Irina G. Gazaryan","orcid":"0000-0002-9670-5579","position":5,"is_corresponding":false},{"id":644388,"name":"Bobby Thomas","orcid":"0000-0001-9244-9726","position":6,"is_corresponding":false},{"id":644383,"name":"Dmitry M. Hushpulian","orcid":"0000-0002-2171-9896","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-18T23:45:22.477398Z","pmid":"33897412","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":[]}