Neuroblastoma (NB) is the most common extracranial solid tumour in childhood, and MYCN-amplification is one of the strongest predictors of poor prognosis. MYCN-amplified NB cells show chronic oxidative stress and are therefore dependent on adaptive stress response pathways, which could be therapeutically targeted. APR-246, a drug that induces oxidative stress and ferroptosis, has shown preclinical promise, but what determines the sensitivity remains unclear. A genome-wide CRISPR/Cas9 screen under APR-246 treatment identified AVEN as a candidate gene whose loss increased APR-246 sensitivity. Validation by shRNA knockdown in MYCN-amplified (SKNDZ) and non MYCN-amplified (SHSY5Y) NB cell lines confirmed that AVEN depletion increased the sensitivity to APR-246, while AVEN overexpression increased the resistance. SKNDZ cells showed higher basal ROS levels and increased APR-246 sensitivity. AVEN loss further disturbed redox balance in this context. AVEN depletion also affected proliferation and increased the sensitivity to the ferroptosis inducer RSL3. This phenotype was rescued by Ferrostatin-1 (ferroptosis inhibitor) but not by apoptosis or necroptosis inhibitors, indicating a role in ferroptosis protection. Phosphoproteomic and transcriptomic assays revealed activation of stress-response signalling pathways, suppression of the AKT/mTOR pathway and a general downregulation of proliferative and biosynthetic pathways following AVEN depletion. These findings support AVEN as a regulator of ferroptosis resistance in NB, especially in the context of MYCN-amplification.