2. Academic Validation
  3. HSP90 deficiency promotes cholesteryl ester accumulation in lipid droplets via endocytosis of low-density lipoprotein

HSP90 deficiency promotes cholesteryl ester accumulation in lipid droplets via endocytosis of low-density lipoprotein

  • Commun Biol. 2025 Aug 6;8(1):1169. doi: 10.1038/s42003-025-08562-2.
Chengxin Ma 1,  Xinmeng Che 1,  Yan Liang 1,  Jiacheng Li 1,  Kuan Yu 1,  Tong-Jin Zhao 1 2,  Peng Li 3 4 5,  Feng-Jung Chen 6 7
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetics and Development of Complex Phenotypes, Institute of Metabolism and Integrative Biology, School of Life Sciences, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 Shanghai Qi Zhi Institute, Shanghai, China.
  • 3 Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetics and Development of Complex Phenotypes, Institute of Metabolism and Integrative Biology, School of Life Sciences, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China. li-peng@mail.tsinghua.edu.cn.
  • 4 Shanghai Qi Zhi Institute, Shanghai, China. li-peng@mail.tsinghua.edu.cn.
  • 5 State Key Laboratory of Membrane Biology and Tsinghua-Peking Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China. li-peng@mail.tsinghua.edu.cn.
  • 6 Shanghai Key Laboratory of Metabolic Remodeling and Health, State Key Laboratory of Genetics and Development of Complex Phenotypes, Institute of Metabolism and Integrative Biology, School of Life Sciences, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China. derrick_chen@fudan.edu.cn.
  • 7 Shanghai Qi Zhi Institute, Shanghai, China. derrick_chen@fudan.edu.cn.
PMID: 40770403 DOI: 10.1038/s42003-025-08562-2
Abstract

The size and number of lipid droplets (LDs), as intracellular lipids storage organelles, are closely correlated to lipid metabolism. However, the regulation of lipid metabolism is still unclear. Here, based on changes in three LD phenotypic indicators, including LD number, average LD area, and total LD amount in a cell, we establish an imaging-based high-throughput screen on a compound library. We identify that HSP90 inhibitors effectively promote lipid accumulation, as demonstrated by the increased total amount of cellular LDs. Both gene silencing and functional inhibition of HSP90 result in LD accumulation. This LD phenotype induced by HSP90 knockdown is autophagy-independent and requires functional lysosomal pathway. We further identify cholesteryl ester (CE) as the major lipid class accumulated following HSP90 deficiency. Further work demonstrates that the increase in CE is the result of enhanced exogenous lipoprotein uptake via clathrin-mediated endocytosis and requires Cholesterol esterification mediated by ACAT1. Overall, our data reveal that HSP90 regulates Cholesterol metabolism by modifying cellular LDL uptake ability and intracellular lipid trafficking.

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