Accessibility-guided targeting of NRF2-responsive long noncoding RNA NMRAL2P alters a distinct gene expression program and reduces non-small cell lung cancer proliferation

Aberrant activation of the antioxidant transcription factor NRF2 promotes non-small cell lung cancer (NSCLC) survival and therapy resistance, but downstream effectors beyond redox regulation remain incompletely defined. Transcriptome profiling of lung and NSCLC cells identified the pseudogene-derived long noncoding RNA LOC344887/NMRAL2P as consistently associated with NRF2 activity. The NMRAL2P locus produces three predominant, nuclear-localized isoforms whose expression depends on NRF2 across normal lung, lung adenocarcinoma, and lung squamous carcinoma cells. In-cell SHAPE-MaP identified accessible regions within NMRAL2P transcripts, guiding antisense gapmer design. NMRAL2P depletion inhibited NSCLC cell proliferation and increased sensitivity to cisplatin. Transcriptome analysis revealed that NMRAL2P depletion altered a restricted gene expression program involving cell adhesion and MAPK signaling, with responses distinct from those observed following NRF2 depletion. Core NRF2 antioxidant target genes were largely unaffected by NMRAL2P depletion. These findings support a model in which NRF2 induces NMRAL2P to sustain a distinct gene expression program that contributes to NSCLC proliferation and survival. NMRAL2P represents an RNA effector downstream of NRF2 that links oncogenic NRF2 activity to cellular functions beyond canonical antioxidant responses, providing a potential point of intervention in NRF2-active lung cancers and motivating further investigation of the mechanisms connecting this nuclear RNA to signaling pathways.