Super-enhancer–mediated SMAD3–NR2F2–ID3 transcriptional complex orchestrates Osimertinib resistance in non-small cell lung cancer

Osimertinib resistance remains a major challenge in the treatment of non–small cell lung cancer (NSCLC). Here, we identify an unconventional super-enhancer–driven transcriptional module, composed of SMAD3, NR2F2, and ID3, in which ID3 functions as a transcriptional co-factor to sustain resistance. Mechanistically, ID3 directly interacts with SMAD3 and NR2F2, inducing conformational rearrangements that enhance their DNA-binding affinity to enhancer regions, thereby increasing transcriptional activity. This ID3-SMAD3/NR2F2 complex selectively activates EPAS1, which in turn promotes neuroendocrine differentiation and suppresses ferroptosis, thereby maintaining the resistant phenotype. Disruption of this complex abrogates EPAS1 expression and restores Osimertinib sensitivity in preclinical models. Our findings uncover a previously unrecognized role of ID3 as a transcriptional co-factor and highlight the super-enhancer–driven SMAD3–NR2F2–ID3–EPAS1 axis as a promising therapeutic target to overcome Osimertinib resistance in NSCLC.