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Nuclear factor erythroid 2\u2010related factor 2 (NRF2) is a redox\u2010regulated transcription factor frequently dysregulated in non\u2010small cell lung cancer (NSCLC), leading to aggressive disease and resistance to therapy. In this study, we analyzed circulating cell\u2010free tumor DNA from a real\u2010world cohort to characterize clinicopathological features and identify risk factors associated with oncogenic NRF2 activation in inoperable NSCLC. Key findings were further validated using retrospective datasets. Our results demonstrate that NRF2 pathway\u2010mutated NSCLC represents a smoking\u2010associated, high\u2010risk molecular subtype frequently accompanied by detrimental SMARCA4 mutations. Importantly, these co\u2010occurring mutations cumulatively worsen clinical outcomes independently of other risk factors. We show that NRF2\u2010mutated tumors generally exhibit lower leukocyte infiltration, while high tumor mutation burden independently correlates with increased cytotoxic T lymphocyte density, regardless of NRF2 status. Furthermore, our data indicate that NRF2 activation can be reliably identified through immunohistochemical detection of protein expression of markers AKR1B10 and AKR1C1, both of which correlate with inferior outcomes. As mutations in NRF2\u2010regulating tumor suppressors\n                    <jats:italic>KEAP1<\/jats:italic>\n                    and\n                    <jats:italic>CUL3<\/jats:italic>\n                    are not confined to specific hotspot regions, our findings advocate for a multimodal profiling approach combining somatic mutation assessment with protein or transcriptomic evaluation of NRF2 targets. This comprehensive strategy effectively identifies oncogenic NRF2 hyperactivity, enhancing diagnostic accuracy and clinical decision\u2010making in NSCLC management. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70043","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:00:24Z","timestamp":1772989224000},"page":"164-181","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinicopathological characteristics of patients with inoperable non\u2010small cell lung cancer harboring circulating\n                    <scp>NRF2<\/scp>\n                    pathway mutations"],"prefix":"10.1002","volume":"269","author":[{"given":"Jouni","family":"H\u00e4rk\u00f6nen","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences, A.I. 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Virtanen Institute for Molecular Sciences University of Eastern Finland  Kuopio Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuomas","family":"Tikkanen","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences University of Eastern Finland  Kuopio Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2801-8902","authenticated-orcid":false,"given":"Ina","family":"P\u00f6hner","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Health Sciences University of Eastern Finland  Kuopio Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tommi","family":"Patinen","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, A.I. 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