Advanced Science, 5 June, 2025, DOI：https://doi.org/10.1002/advs.202503473

Lipid Droplet-Organized MDM2-Mediated P53 Degradation: A Metabolic Switch Governing Diet-Driven Tumor Progression

Haiyang Liu, Lin Jing, Yixin Li, Jinxing Zhou, Xiaohui Cui, Sen Li, Shijie Yang, Fangming Kan, Junfeng Du, Wentao Zhong, Sheng Yu, Ning Wang, Xing Jia, Junhui Li, Pan Nie, Zhenzhong Chen, Ying Han, Lingxi Jiang, Xiyun Yan, Hongxia Duan, Baiyong Shen

Abstract

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.

Article link：https://advanced.onlinelibrary.wiley.com/doi/10.1002/advs.202503473