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journal article·2025-08Open access

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

Advanced Science· Volume 12· Issue 32
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Source abstract

Abstract

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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Research context

OpenAlex topics: Cancer, Hypoxia, and Metabolism · Lipid metabolism and biosynthesis · Cancer-related Molecular Pathways

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

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

Research Institute of Pancreatic Diseases Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms Shanghai Jiao Tong University School of Medicine Shanghai 200025 China

State Key Laboratory of Systems Medicine for Cancer Institute of Translational Medicine Shanghai Jiao Tong University Shanghai 200025 China

CAS Engineering Laboratory for Nanozyme Key Laboratory of Biomacromolecules (CAS) CAS Center for Excellence in Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 PR China

Nanozyme Laboratory in Zhongyuan Henan Academy of Innovations in Medical Science Zhengzhou 451163 China

University of Chinese Academy of Sciences Beijing 100049 China

National Laboratory of Macromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101 China

National Institute of Biological Sciences Beijing 102206 China

School of Information Science and Technology Beijing Forestry University Beijing 100083 China

Engineering Research Center for Forestry‐oriented Intelligent Information Processing of National Forestry and Grassland Administration Beijing 100083 China

Department of Biochemistry & Immunology Capital Institute of Pediatrics Beijing 100020 China

Medical Department of General Surgery The 1st Medical Center Chinese PLA General Hospital Beijing 100853 China

Department of General Surgery The 7th Medical Center Chinese PLA General Hospital Beijing 100700 China

The Second School of Clinical Medicine Southern Medical University Guangdong 510515 China

The Second School of Clinical Medicine Southern Medical University Guangzhou 510515 China

Center for Biological Imaging, Core Facilities for Protein Science, Institute of Biophysics CAS Beijing 100101 China

Funding

National Natural Science Foundation of China

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