2. Academic Validation
  3. mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway

mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway

  • Mol Cell. 2026 Apr 16;86(8):1546-1559.e8. doi: 10.1016/j.molcel.2026.03.019.
Thomas A O'Loughlin 1,  John S Stiles 2,  Pritika Acharya 3,  Abolfazl Arab 4,  Laine Goudy 5,  Raymond Dai 6,  Ashir A Borah 2,  William A Weiss 7,  Uche N Medoh 2,  Luke A Gilbert 8
Affiliations

Affiliations

  • 1 Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marie-Josee and Henry R. Kravis Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].
  • 2 Arc Institute, Palo Alto, CA 94304, USA.
  • 3 Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marie-Josee and Henry R. Kravis Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 4 Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Arc Institute, Palo Alto, CA 94304, USA; Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 5 Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Arc Institute, Palo Alto, CA 94304, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
  • 6 Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Arc Institute, Palo Alto, CA 94304, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 7 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 8 Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Arc Institute, Palo Alto, CA 94304, USA. Electronic address: [email protected].
PMID: 41997112 DOI: 10.1016/j.molcel.2026.03.019
Abstract

Aberrant activation of the PI3K/Akt/mTOR signaling pathway is a common feature of Cancer, but while mTOR kinase represents an attractive drug target, mTOR inhibitors have not seen broad success as single agents. To identify strategies to enhance the utility of third-generation bi-steric mTORC1 inhibitors, we performed genome-scale CRISPR interference chemogenomics screens, which revealed that mTORC1 inhibitor-mediated cytostasis leaves cells exquisitely dependent on the lipid peroxide scavenging enzyme GPX4. Mechanistically, using unbiased CRISPR activation chemogenomics screens, we demonstrate that mTORC1-dependent control of Ferroptosis occurs, in part, through regulation of SCARB1 expression. Specifically, we find that the high-density lipoprotein (HDL) can suppress Ferroptosis through interaction with its receptor SCARB1 and delivery of vitamin E to target cells. Our work highlights combining mTORC1 with GPX4 inhibition as one of the most promising combinatorial approaches for mTOR-targeted Cancer therapies and defines an HDL-SCARB1 ferroptosis-suppression system that is regulated by mTORC1 activity.

Keywords

GPX4; HDL; SCARB1; antioxidant; cancer; cell biology; ferroptosis; functional genomics; lipoprotein; mTOR; tocopherol; vitamin E.

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