TRIM26-mediated NKRF degradation drives Osimertinib resistance through SNRPD2-dependent stress granule formation in...

Osimertinib is the standard first-line therapy for EGFR-mutant lung adenocarcinoma; however, the inevitable development of acquired resistance leads to disease progression and treatment failure. While established resistance mechanisms primarily involve genetic alterations, stress-adaptive pathways, particularly stress granule-mediated therapeutic tolerance, remain poorly understood. This study aims to elucidate the transcriptional and post-translational mechanisms governing stress granule-mediated survival and their contribution to Osimertinib resistance in lung adenocarcinoma. We identify NF-κB repressing factor (NKRF) as a critical suppressor of Osimertinib resistance, whose expression is markedly reduced in resistant lung adenocarcinoma cells. Restoration of NKRF significantly sensitized resistant cells to Osimertinib in vitro and inhibited tumor growth in xenograft models. Mechanistically, NKRF directly repressed transcription of the ribonucleoprotein component Small nuclear ribonucleoprotein D2 (SNRPD2), thereby constraining stress granule formation and attenuating drug tolerance. We further demonstrate that the E3 ubiquitin ligase TRIM26 interacts with NKRF and promotes its K48-linked ubiquitination at Lys411, leading to proteasomal degradation. This process sustains SNRPD2 expression and enhances stress granule assembly. Genetic depletion of TRIM26 restored NKRF stability, suppressed stress granule formation, and re-sensitized resistant tumors to Osimertinib, effects that were abrogated by concomitant NKRF silencing. Collectively, this study defines a previously unrecognized TRIM26/NKRF/SNRPD2 regulatory axis that integrates ubiquitin-mediated proteostasis with transcriptional control of stress granule dynamics. This work provides mechanistic insight into stress-adaptive Osimertinib resistance and identifies potential therapeutic targets for overcoming resistance in EGFR-mutant lung adenocarcinoma.