Liu Haiyang, Jing Lin, Li Yixin, Zhou Jinxing, Cui Xiaohui, Li Sen, Yang Shijie, Kan Fangming, Du Junfeng, Zhong Wentao, Yu Sheng, Wang Ning, Jia Xing, Li Junhui, Nie Pan, Chen Zhenzhong, Han Ying, Jiang Lingxi, Yan Xiyun, Duan Hongxia, Shen Baiyong
Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Adv Sci (Weinh). 2025 Aug;12(32):e03473. doi: 10.1002/advs.202503473. Epub 2025 Jun 5.
TP53 inactivation in human cancers often results from MDM2/MDMX overexpression, yet therapeutic targeting remains challenging owing to incomplete mechanistic understanding. Lipid droplet (LD) enrichment is identified as a key trigger for MDM2-mediated p53 degradation. High-fat diet (HFD)-induced LD accumulation in tumor cells elevates LD-surface MDM2 through Cyb5r3-Myh9 interactions, which recruit cytoplasmic p53/Myh9 complexes to LDs. This spatial proximity enhances MDM2-p53 binding, accelerating its ubiquitination and proteasomal degradation. Degraded p53 releases the RPS3A-C/EBPβ complex, upregulating LD-promoting factors such as CD36 to establish a cell-autonomous feed-forward loop. Critically, pharmacological LD reduction (via lipogenesis inhibitors) or switching of tumor-bearing mice from an HFD to a normal diet restores p53 levels and suppresses tumor growth. These findings delineate a lipid-driven regulatory axis in which LD biogenesis initiates MDM2-dependent p53 destruction, reshaping tumor cell lipid metabolism. This mechanism links dietary lipids to oncogenesis through organelle-specific protein trafficking and provides a therapeutic rationale for targeting lipid metabolism in tumors. This study resolves critical gaps in p53 regulation while proposing dual intervention strategies: disrupting LD-MDM2 colocalization and modulating lipid availability.
人类癌症中的TP53失活通常源于MDM2/MDMX的过表达，但由于对其机制的理解不完整，治疗靶向仍然具有挑战性。脂滴（LD）富集被确定为MDM2介导的p53降解的关键触发因素。高脂饮食（HFD）诱导肿瘤细胞中LD积累，通过Cyb5r3-Myh9相互作用提高LD表面的MDM2水平，从而将细胞质中的p53/Myh9复合物募集到LDs。这种空间上的接近增强了MDM2与p53的结合，加速了其泛素化和蛋白酶体降解。被降解的p53释放RPS3A-C/EBPβ复合物，上调如CD36等促进LD生成的因子，从而建立一个细胞自主的前馈回路。至关重要的是，通过药理学方法减少LD（通过脂肪生成抑制剂）或使荷瘤小鼠从HFD转换为正常饮食可恢复p53水平并抑制肿瘤生长。这些发现描绘了一个脂质驱动的调节轴，其中LD生物合成引发MDM2依赖的p53破坏，重塑肿瘤细胞脂质代谢。该机制通过细胞器特异性蛋白转运将饮食中的脂质与肿瘤发生联系起来，并为靶向肿瘤脂质代谢提供了治疗依据。这项研究填补了p53调节方面的关键空白，同时提出了双重干预策略：破坏LD与MDM2的共定位以及调节脂质可用性。
