HNRNPD Induces Radioresistance in Nasopharyngeal Carcinoma by Sequestering GRAMD4 mRNA in Stress Granules

ABSTRACT Radiotherapy resistance remains a major obstacle in nasopharyngeal carcinoma (NPC). Stress granules (SGs), dynamic cytoplasmic ribonucleoprotein condensates, have been linked to therapy resistance, but their role in NPC radioresistance remains unclear. Here, we show that SGs are key mediators of NPC radioresistance. Radioresistant NPC cells displayed markedly enhanced SG formation in a dose‐ and time‐dependent manner, whereas pharmacological inhibition with ISRIB or genetic disruption of G3BP1 significantly sensitized cells to irradiation in vitro and in vivo. Integrated transcriptomic and proteomic analyses identified heterogeneous nuclear ribonucleoprotein D (HNRNPD) as a critical SG‐associated RNA‐binding protein upregulated in resistant cells and associated with poor prognosis. Functionally, HNRNPD promoted radioresistance by suppressing apoptosis, whereas its depletion restored radiosensitivity. Mechanistically, HNRNPD underwent RNA‐dependent phase separation through its C‐terminal intrinsically disordered region and interacted with G3BP1 to facilitate SG assembly. Irradiation promoted cytoplasmic accumulation of HNRNPD, while the p37 isoform preferentially bound G3BP1 and functionally drove SG formation. HNRNPD further bound GRAMD4 mRNA via its RRM1 domain and sequestered it in SG‐associated compartments, thereby repressing GRAMD4 translation, suppressing mitochondrial apoptosis, and promoting survival. Restoration of GRAMD4 abrogated HNRNPD‐induced radioresistance. Together, these findings establish the HNRNPD–SG–GRAMD4 axis as a key determinant of NPC radioresistance and a potential therapeutic target for radiosensitization.