Disruption of the KLHL37–N-Myc complex restores N-Myc degradation and arrests neuroblastoma growth in mouse models

MYCN amplification accounts for the most common genetic aberration in neuroblastoma and strongly predicts the aggressive progression and poor clinical prognosis. However, clinically effective therapies that directly target N-Myc activity are limited. N-Myc is a transcription factor, and its stability are tightly controlled by ubiquitination-dependent proteasomal degradation. Here, we discovered that Kelch-like protein 37 (KLHL37) played a crucial role in enhancing the protein stability of N-Myc in neuroblastoma. KLHL37 directly interacted with N-Myc to disrupt the N-Myc/FBXW7 interaction, thereby stabilizing N-Myc and enabling tumor progression. Suppressing KLHL37 effectively induced the degradation of N-Myc and exhibited a profound inhibitory effect on the growth of MYCN-amplified neuroblastoma. Notably, we identified RTA-408 as an inhibitor of KLHL37 to disrupt KLHL37-N-Myc complex, promoting the degradation of N-Myc and suppressing neuroblastoma in vivo and in vitro. Moreover, we elucidated the therapeutic potential of RTA-408 for neuroblastoma by utilizing the PDC and PDX tumor models. RTA408's anti-tumor effects may not be exclusively via KLHL37, and specific KLHL37 inhibitors are expected to be developed in the future. These findings not only uncover the biological function of KLHL37 in regulating N-Myc stability, but also indicate that KLHL37 inhibition is a promising therapeutic regimen for neuroblastoma, especially in MYCN-amplified patients.