2. Academic Validation
  3. mTOR inhibition reprograms cellular lipid homeostasis by inducing alternative lipid uptake and promoting cholesterol transport

mTOR inhibition reprograms cellular lipid homeostasis by inducing alternative lipid uptake and promoting cholesterol transport

  • Mol Cell. 2025 Sep 18;85(18):3486-3504.e7. doi: 10.1016/j.molcel.2025.08.021.
Sejeong Shin 1,  Min-Joon Han 2,  Ishika Patel 3,  Alia M Welsh 4,  Maria Sverdlov 5,  Wonhwa Cho 6,  Stephanie M Cologna 6,  Philippe P Roux 7,  Sang-Oh Yoon 8
Affiliations

Affiliations

  • 1 Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL 60612, USA.
  • 2 Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 3 Department of Biological Sciences, College of Liberal Arts and Sciences, University of Illinois Chicago, Chicago, IL 60607, USA.
  • 4 Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL 60612, USA.
  • 5 Research Histology Core, Research Resources Center, and Department of Pathology, University of Illinois Chicago, Chicago, IL 60612, USA.
  • 6 Department of Chemistry, College of Liberal Arts and Sciences, University of Illinois Chicago, Chicago, IL 60607, USA.
  • 7 Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada; Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.
  • 8 Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, IL 60612, USA. Electronic address: syoon1@uic.edu.
PMID: 40972529 DOI: 10.1016/j.molcel.2025.08.021
Abstract

The mechanistic target of rapamycin (mTOR) is a key regulator of lipid homeostasis by controlling processes including lipid uptake and biosynthesis. mTOR dysregulation and consequent altered lipid metabolism are common in various diseases, including cancers, making mTOR a promising therapeutic target. Therefore, it is crucial to understand how mTOR activation and inhibition reprogram lipid homeostasis. In human Cancer cell lines, mTOR inhibition induces alternative lipid uptake through translation eukaryotic initiation factor 3D (eIF3D)-mediated low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) increase and activates liver X receptor β (LXRβ), promoting Cholesterol release from lysosomes and its transport to the plasma membrane via Niemann-Pick disease type C (NPC) intracellular Cholesterol transporter 1 (NPC1). This signaling supports tumor cell survival and stress resistance. In mouse xenograft models, combining mTOR inhibition with LRP6 knockdown or NPC1 targeting significantly suppresses tumor growth. Our findings highlight mTOR feedback signaling in reprogramming lipid homeostasis and its therapeutic potential to treat diseases characterized by dysregulated mTOR.

Keywords

AKT; IGF1R; LRP6; NPC1; cholesterol; mTOR.

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