Collectively, our data indicate that LRP8 is required to prevent ferroptosis by maintaining high levels of GPX4 in MYCN‐amplified orthotopic neuroblastoma models and suggest that inhibition of the SELENOP/LRP8 axis as a novel and selective strategy to trigger ferroptosis and thereby limit tumor growth in highly aggressive and hard to treat MYCN‐amplified neuroblastoma cells (Fig 4I). Here, LRP8 is linked to neoplasm.