Patients with polycystic kidney disease (PKD) encounter a high risk of clear cell renal cell carcinoma (ccRCC), a malignant tumor with dysregulated lipid metabolism. SET domain–containing 2 (SETD2) has been identified as an important tumor suppressor and an immunosuppressor in ccRCC. However, the role of SETD2 in ccRCC generation in PKD remains largely unexplored. Herein, we perform metabolomics, lipidomics, transcriptomics and proteomics within SETD2 loss induced PKD-ccRCC transition mouse model. Our analyses show that SETD2 loss causes extensive metabolic reprogramming events that eventually results in enhanced sphingomyelin biosynthesis and tumorigenesis. Clinical ccRCC patient specimens further confirm the abnormal metabolic reprogramming and sphingomyelin accumulation. Tumor symptom caused by Setd2 knockout is relieved by myriocin, a selective inhibitor of serine-palmitoyl-transferase and sphingomyelin biosynthesis. Our results reveal that SETD2 deficiency promotes large-scale metabolic reprogramming and sphingomyelin biosynthesis during PKD-ccRCC transition. This study introduces high-quality multi-omics resources and uncovers a regulatory mechanism of SETD2 on lipid metabolism during tumorigenesis.

多囊肾病（PKD）患者罹患透明细胞肾细胞癌（ccRCC）的风险很高，透明细胞肾细胞癌是一种脂质代谢失调的恶性肿瘤。含 SET 结构域 2 (SETD2) 已被确定为 ccRCC 中重要的肿瘤抑制因子和免疫抑制剂。然而，SETD2 在 PKD ccRCC 生成中的作用在很大程度上仍未被探索。在此，我们在 SETD2 丢失诱导的 PKD-ccRCC 过渡小鼠模型中进行代谢组学、脂质组学、转录组学和蛋白质组学。我们的分析表明，SETD2 缺失会导致广泛的代谢重编程事件，最终导致鞘磷脂生物合成和肿瘤发生增强。临床ccRCC患者标本进一步证实了异常的代谢重编程和鞘磷脂积累。Setd2敲除引起的肿瘤症状可通过丝氨酸棕榈酰转移酶和鞘磷脂生物合成的选择性抑制剂缓解。我们的结果表明，SETD2 缺陷在 PKD-ccRCC 转变过程中促进大规模代谢重编程和鞘磷脂生物合成。该研究引入了优质的多组学资源，揭示了SETD2在肿瘤发生过程中脂代谢的调控机制。