ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
Lipid Droplet-Organized MDM2-Mediated P53 Degradation: A Metabolic Switch Governing Diet-Driven Tumor Progression.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.Cellular & molecular immunology · 2026Review
- GDPD5-CD55-EGFR competitive binding axis regulates radioresistance and lipid accumulation in rectal cancer.Cell death & disease · 2026Article
- Article
- OTUD4 regulates pancreatic cancer progression via Hippo/YAP axis.Neoplasia (New York, N.Y.) · 2026Article
- Triglyceride Storage is Upregulated in Different Mouse Non-Melanoma Skin Cancer Cell Lines.microPublication biology · 2026Article
- Lipid Droplet-Organized MDM2-Mediated P53 Degradation: A Metabolic Switch Governing Diet-Driven Tumor Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
Corrections and comments
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Authors and funding
21 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.