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

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

SUBMITTER: Liu H 

PROVIDER: S-EPMC12407345 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature