Related Experiment Video

Updated: Sep 19, 2025

Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy
07:20

Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy

Published on: January 31, 2025

674

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

Haiyang Liu1,2,3, Lin Jing4,5, Yixin Li6,7

  • 1Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 5, 2025
PubMed

Insights

High-fat diets promote cancer by increasing lipid droplets (LDs), which enhance MDM2-mediated p53 degradation. Reducing LDs or dietary fat restores p53 and suppresses tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • TP53 tumor suppressor inactivation is common in cancers, often due to MDM2/MDMX overexpression.
  • The precise mechanisms driving MDM2-mediated p53 degradation, especially in response to metabolic cues, require further elucidation.
  • Lipid metabolism dysregulation is increasingly recognized as a hallmark of cancer, but its direct role in p53 pathway inactivation is not fully understood.

Purpose of the Study:

  • To investigate the role of lipid droplets (LDs) in regulating p53 stability and function in cancer.
  • To elucidate the molecular mechanisms linking high-fat diet (HFD)-induced metabolic changes to p53 degradation.
  • To identify potential therapeutic strategies targeting the interplay between lipid metabolism and p53 pathway in cancer.

Main Methods:

  • Utilized cell culture models and tumor-bearing mice fed high-fat diets.
  • Investigated protein-protein interactions involving MDM2, p53, Cyb5r3, and Myh9 at lipid droplet surfaces.
  • Assessed the impact of pharmacological lipogenesis inhibition and dietary interventions on p53 levels and tumor growth.

Main Results:

  • High-fat diet-induced LD accumulation elevates LD-surface MDM2 via Cyb5r3-Myh9 interactions, promoting p53 degradation.
  • Degraded p53 leads to the release of RPS3A-C/EBPβ, upregulating CD36 and creating a positive feedback loop for LD biogenesis.
  • Pharmacological LD reduction or switching to a normal diet restored p53 levels and suppressed tumor growth.

Conclusions:

  • Lipid droplet biogenesis is a critical trigger for MDM2-dependent p53 destruction, establishing a lipid-driven regulatory axis in cancer.
  • This mechanism links dietary lipids to oncogenesis via organelle-specific protein trafficking, offering a novel therapeutic target.
  • Targeting lipid metabolism, specifically by disrupting LD-MDM2 colocalization or modulating lipid availability, presents a promising dual intervention strategy for cancer therapy.
Keywords:
high‐fat dietslipid dropletsp53 degradation initiationtumor growth

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