LAUSR

Neuroblastoma (NB), a pediatric solid malignancy, is distinguished by hetergenous clinical characteristics, including tumor aggressiveness or spontaneous regression. Nevertheless, the regulatory mechanisms and therapeutic approaches underlying these processes are still mainly unknown. Herein, RAR‐related orphan receptor B (RORB) as a transcription factor repressing nuclear factor kappa B (NF‐κB) signaling involved in lysosomal biogenesis of NB. RORB attenuated the growth, invasiveness, and metastatic spread of NB cells are identified. From a mechanistic perspective, RORB increased the transcription of nuclear receptor subfamily 1 group D member 1 (NR1D1)‐ or RIO kinase 3 (RIOK3)‐ in a circadian clock‐dependent manner, resulting in suppression of NF‐κB activity, subsequent derepression of folliculin (FLCN)‐ or folliculin interacting protein 1 (FNIP1)‐ levels, and decrease of lysosomal biogenesis in NB cells. Meanwhile, in liquid condensates, RNA binding motif protein 10 (RBM10) interacted with RORB to repress its transactivation and exerted oncogenic roles in lysosomal biogenesis and aggressiveness of NB cells. Pre‐clinically, a small peptide is able to block the interaction between RBM10 and RORB, and suppresses lysosomal biogenesis, tumorigenesis, and aggressiveness. High levels of RORB, NR1D1, RIOK3, FLCN, and FNIP1, or low expression of RBM10, are linked to favorable prognosis of clinical NB cases. These results indicate that targeting RBM10‐repressed RORB activity in liquid condensates inhibits lysosomal biogenesis and NB progression via affecting NF‐κB signaling.