Abstract

MYCN -amplified neuroblastoma is one of the most lethal pediatric malignancies, where aberrant N-Myc-driven transcription promotes tumor progression. As direct targeting of N-Myc has proven challenging, current approaches prioritize understanding the mechanisms that regulate its activity, which remain poorly understood. Here, we demonstrate a crucial role of S-acylation in regulating N-Myc transcriptional activity and identify the acyltransferase zinc finger DHHC-type containing 22 (ZDHHC22) as a key regulator of this process. Mechanistically, ZDHHC22 catalyzes the S-acylation of N-Myc, which enhances its transcriptional activity by facilitating the recruitment of coactivators such as TIP60 and GCN5. Furthermore, N-Myc transcriptionally upregulates ZDHHC22, establishing a feedback loop that contributes to chemoresistance in high-risk neuroblastoma. Targeting ZDHHC22 suppresses neuroblastoma cell growth in vitro and in vivo , particularly in refractory patient-derived models. Collectively, our findings uncover a biological function of ZDHHC22 in regulating N-Myc transcriptional activation and indicate that ZDHHC22 is a promising therapeutic target for N-Myc-driven high-risk neuroblastoma, especially in MYCN -amplified patients.