{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:21:43Z","timestamp":1785424903692,"version":"3.56.0"},"reference-count":167,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2026-25485640"],"award-info":[{"award-number":["RS-2026-25485640"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2026-25485640"],"award-info":[{"award-number":["RS-2026-25485640"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Nuclear factor erythroid 2-related factor 2 (NRF2) has traditionally been framed as a Kelch-like ECH-associated protein 1 (KEAP1)-regulated stress-response transcription factor, but three observations now require a broader framework: NRF2 turnover is controlled by parallel E3 ligase systems; transcriptional output can be limited by coactivator assembly despite unchanged NRF2 abundance; and NRF2 activation can be beneficial or harmful depending on disease context, as illustrated by lung cancer models in which NRF2 paradoxically promotes metastasis through BTB and CNC homology 1 (BACH1) stabilization. We synthesize these observations into an NRF2 partner-code framework in which NRF2 acts as a context-dependent transcriptional platform assembled through four partly independent modules: a degradation module (KEAP1; \u03b2-transducin repeat-containing protein, \u03b2-TrCP; HMG-CoA reductase degradation protein 1\/synoviolin 1, Hrd1\/SYVN1; WD repeat-containing protein 23\/DDB1- and CUL4-associated factor 11, WDR23\/DCAF11); a cytoplasmic scaffold module (p62\/sequestosome 1, p62\/SQSTM1; IQ motif-containing GTPase-activating protein 1, IQGAP1; type I phosphatidylinositol 4-phosphate 5-kinase \u03b3\/heat shock protein 27, PIPKI\u03b3\u2013HSP27; peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, PIN1; peptidyl-prolyl isomerase A\/cyclophilin A, PPIA); a nuclear coactivator module at Neh4\/5 (CREB-binding protein\/p300, CBP\/p300; receptor-associated coactivator 3\/steroid receptor coactivator 3, RAC3\/SRC-3; protein arginine methyltransferase 1\/coactivator-associated arginine methyltransferase 1, PRMT1\/CARM1; Mediator complex subunit 16, MED16); and a DNA\/chromatin module at Neh1 (small musculoaponeurotic fibrosarcoma [Maf] proteins, BACH1, and chromodomain helicase DNA-binding protein 6, CHD6). Mapping 22 partners onto the Neh-domain architecture identifies approximately 25 pharmacologically addressable interfaces, stratified into four translational tiers. The framework reframes NRF2 pharmacology around one principle: the most actionable target is often a partner rather than NRF2 itself, with disease context dictating the direction of modulation. We close with five testable hypotheses and a partner-code decision matrix linking disease, biomarker, and candidate target.<\/jats:p>","DOI":"10.3390\/antiox15060759","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T08:22:56Z","timestamp":1781684576000},"page":"759","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond KEAP1: The Context-Specific NRF2 Partner Code in Disease and Therapy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9267-9158","authenticated-orcid":false,"given":"Seung-Jin","family":"Kwag","sequence":"first","affiliation":[{"name":"Department of Surgery, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"},{"name":"Institute of Medical Science, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"},{"name":"Biomedical Research Institute, Gyeongsang National University Hospital, 79 Gangnam-ro, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6113-7252","authenticated-orcid":false,"given":"Jin-Kwon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Surgery, Gyeongsang National University Changwon Hospital, 11 Samjungja-ro, Changwon 51472, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9749-7505","authenticated-orcid":false,"given":"Seung-Jun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Surgery, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"},{"name":"Institute of Medical Science, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8798-7438","authenticated-orcid":false,"given":"Jeongyun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Convergence Medical Sciences, Gyeongsang National University, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8571-2722","authenticated-orcid":false,"given":"Young-Sool","family":"Hah","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, Gyeongsang National University College of Medicine, 816-15 Jinju-daero, Jinju 52727, Republic of Korea"},{"name":"Biomedical Research Institute, Gyeongsang National University Hospital, 79 Gangnam-ro, Jinju 52727, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9926","DOI":"10.1073\/pnas.91.21.9926","article-title":"Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2\/AP1 repeat of the beta-globin locus control region","volume":"91","author":"Moi","year":"1994","journal-title":"Proc. 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