高危神经母细胞瘤表现出甾醇和非甾醇异戊烷骨架化反应活性，从而产生了甾醇和非甾醇异戊烷。更好地了解这种代谢重构对神经母细胞瘤发展的贡献，可以帮助鉴定潜在的预防和治疗策略。我们在此报告了甾醇和非甾醇己二烯基焦磷酸分支都是维持神经母细胞瘤细胞生长的关键。使用一种降低胆固醇药物西伐他汀阻断甾体醇异戊烷骨架化反应导致神经母细胞瘤细胞系异移植、来源于患者的异种移植模型（PDX）和TH－MYCN转基因小鼠模型的神经母细胞瘤生长受限。转录组分析表明，维持FOX M1介导的有丝分裂转录方案需要甾体醇异戊烷骨架化反应。高FOX M1表达有助于他汀抗药性，并引起了西伐他汀抑制和FOX M1抑制联合治疗的治疗易感性。此外，咖啡因协同西伐他汀通过阻断西伐他汀诱导的维生素酸异戊烷骨架化反应的反馈激活来抑制神经母细胞瘤细胞和PDX肿瘤的生长。咖啡因的这一功能依赖于其作为腺苷受体拮抗剂的作用，而阿昔洛林，一种帕金森病的附加药物，可以复制咖啡因与西伐他汀的协同作用。本研究揭示了FOX M1介导的有丝分裂程序是癌症治疗中甾体醇靶点的分子目标，并鉴定了可以最大化他汀治疗效果的药物类别，这对于高危神经母细胞瘤的治疗具有重要意义。

High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and non-sterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and non-sterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth. Blocking the mevalonate pathway by simvastatin, a cholesterol-lowering drug, impeded neuroblastoma growth in neuroblastoma cell line xenograft, patient-derived xenograft (PDX), and TH-MYCN transgenic mouse models. Transcriptional profiling revealed that the mevalonate pathway was required to maintain the FOXM1-mediated transcriptional program that drives mitosis. High FOXM1 expression contributed to statin resistance and led to a therapeutic vulnerability to the combination of simvastatin and FOXM1 inhibition. Furthermore, caffeine synergized with simvastatin to inhibit the growth of neuroblastoma cells and PDX tumors by blocking statin-induced feedback activation of the mevalonate pathway. This function of caffeine depended on its activity as an adenosine receptor antagonist, and the A2A adenosine receptor antagonist istradefylline, an add-on drug for Parkinson's disease, could recapitulate the synergistic effect of caffeine with simvastatin. This study reveals that the FOXM1-mediated mitotic program is a molecular statin target in cancer and identifies classes of agents for maximizing the therapeutic efficacy of statins with implications for treatment of high-risk neuroblastoma.