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 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.