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SCD1 and SCD5 modulate PARP-dependent DNA repair via fatty acid desaturation in glioblastoma.

Overview

Authors: Hayk Mnatsakanyan1,2, Alessandro Sammarco3, Abigail Hewett1, Rami Awwad1, Elie Roumieh1, Caline Pechdimaljian1, Cagri Cakici1,2, Caroline M Spangler1, Yana Azar1, Richa Pradhan1, Baolong Su4,5, Kevin J Williams4,5, Steven J Bensinger3,4, Christian E Badr1,2,6
ORCID iDs: Hayk Mnatsakanyan, Cagri Cakici, Kevin J Williams, Christian E Badr
  1. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
  2. Neuroscience Program, Harvard Medical School, Boston, MA, USA
  3. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA
  4. UCLA Lipidomics Laboratory, University of California, Los Angeles, Los Angeles, CA, USA
  5. Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
  6. Lead contact
Institutions: Harvard University (United States); Massachusetts General Hospital (United States); University of California, Los Angeles (United States)
Journal: Cell reports, volume 45, issue 4, article 117223
Dates: published online 13 April 2026; in print April 2026
Type: Research article · Language: English
License: CC BY-NC
Identifiers: DOI 10.1016/j.celrep.2026.117223 · PMID 41979920 · PMCID PMC13181748 · OpenAlex W4412676968
Open access: gold, a free copy (OpenAlex)
Preprint: doi:10.1101/2025.07.23.666454
Status: code on request
Categories: other condition (population)
Methods: Statistics, Evoked potentials, fMRI & imaging
Keywords: DNA repair, Fatty acid desaturation, lipid metabolism, Stearoyl-coa Desaturase, Glioma Stem Cells, Parp1, Parthanatos, Cerebral Organoids, Cp: Cancer, Cp: Metabolism
Topic: Mitochondrial Function and Pathology (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: National Cancer Institute (P50 CA165962); NINDS NIH HHS (R01 NS113822); U.S. Department of Defense; US Department of Defense Peer Reviewed Cancer Research Program (CA191075); National Institute of Neurological Disorders and Stroke (R01 NS113822); National Institutes of Health; Ivy Foundation
Citations: cited by 8 papers (Europe PMC); 64 references in the paper
Research resources: AIF RRID:AB_10634755, PARP1 RRID:AB_10698017, NG2 RRID:AB_10870987, GFP RRID:AB_10979281, Anti-rabbit IgG, HRP-linked RRID:AB_2099233, GAPDH RRID:AB_2107436, γH2A.X RRID:AB_2118009, β-Actin RRID:AB_2242334, NFH RRID:AB_2313552, Goat anti-mouse AF 488 RRID:AB_2534069, Goat anti-rabbit AF 647 RRID:AB_2535813, Goat anti-mouse Biotin-XX RRID:AB_2536430, Goat anti-rabbit Biotin-XX RRID:AB_2536431, LC3 A/B RRID:AB_2617131, β-Tubulin RRID:AB_2715541, SCD1 RRID:AB_2723611, KI67 RRID:AB_2797703, SCD5 RRID:AB_2805291, TBP RRID:AB_2881562, Anti-mouse IgG, HRP-linked RRID:AB_330924, OLIG2 RRID:AB_3670559, PAR RRID:AB_3716623, R RRID:SCR_001905, ImageJ FIJI RRID:SCR_002285, BioRender RRID:SCR_018361, RRID:SCR_027865

Abstract

Glioblastoma (GBM) relies on fatty acid metabolism for aggressive growth. This study identifies stearoyl-CoA desaturase-5 (SCD5), a brain-enriched isoform, as a critical driver of glioblastoma stem cell (GSC) maintenance and genomic stability. While SCD1’s role in GBM is well-established, our research reveals that SCD5 plays a non-redundant role by preferentially desaturating C18:0 and uniquely remodeling sphingolipids. Genetic silencing of SCD5 disrupts the cell cycle, impairs DNA repair, and triggers parthanatos—a form of cell death caused by PARP1 hyperactivation. Mechanistically, loss of SCD activity or saturated fatty acid accumulation triggers PARP1 hyperactivation and subsequent degradation, depleting RAD51 to compromise homologous recombination and induce parthanatos. These findings uncover a lipid-mediated vulnerability in GBM, linking fatty acid desaturation to PARP1-dependent genome integrity. Targeting SCD5 may offer a therapeutic strategy to eliminate therapy-resistant GSCs and enhance the efficacy of genotoxic or immunotherapeutic interventions.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

Datasets cited

Data and code availability

RNA-seq data have been deposited in GEO: GSE316537 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE316537) and are publicly available as of the date of publication. The raw shotgun lipidomics data are available in spreadsheet 1.

Microscopy and immunoblot data reported in this paper will be shared by the lead contact upon request

This paper does not report any original code.

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 10 keywords, 7 funders, 64 references, 26 RRIDs.

Cite

This paper

Mnatsakanyan, H., Sammarco, A., Hewett, A., Awwad, R., Roumieh, E., Pechdimaljian, C., Cakici, C., Spangler, C. M., Azar, Y., Pradhan, R., Su, B., Williams, K. J., Bensinger, S. J., & Badr, C. E. (2026). SCD1 and SCD5 modulate PARP-dependent DNA repair via fatty acid desaturation in glioblastoma. Cell reports, 45(4), 117223. https://doi.org/10.1016/j.celrep.2026.117223

BibTeX

@article{mnatsakanyan2026scd1,
author = {Mnatsakanyan, Hayk and Sammarco, Alessandro and Hewett, Abigail and Awwad, Rami and Roumieh, Elie and Pechdimaljian, Caline and Cakici, Cagri and Spangler, Caroline M and Azar, Yana and Pradhan, Richa and Su, Baolong and Williams, Kevin J and Bensinger, Steven J and Badr, Christian E},
title = {{SCD1 and SCD5 modulate PARP-dependent DNA repair via fatty acid desaturation in glioblastoma}},
journal = {Cell reports},
year = {2026},
month = apr,
volume = {45},
number = {4},
pages = {117223},
publisher = {Cell Press},
issn = {2211-1247},
doi = {10.1016/j.celrep.2026.117223},
url = {https://doi.org/10.1016/j.celrep.2026.117223},
pmid = {41979920},
pmcid = {PMC13181748}
}

RIS

TY - JOUR
AU - Mnatsakanyan, Hayk
AU - Sammarco, Alessandro
AU - Hewett, Abigail
AU - Awwad, Rami
AU - Roumieh, Elie
AU - Pechdimaljian, Caline
AU - Cakici, Cagri
AU - Spangler, Caroline M
AU - Azar, Yana
AU - Pradhan, Richa
AU - Su, Baolong
AU - Williams, Kevin J
AU - Bensinger, Steven J
AU - Badr, Christian E
TI - SCD1 and SCD5 modulate PARP-dependent DNA repair via fatty acid desaturation in glioblastoma
T2 - Cell reports
J2 - Cell Rep
PY - 2026
DA - 2026/04/13
VL - 45
IS - 4
SP - 117223
SN - 2211-1247
PB - Cell Press
DO - 10.1016/j.celrep.2026.117223
UR - https://doi.org/10.1016/j.celrep.2026.117223
LA - en
ER -

CSL-JSON

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