2. Academic Validation
  3. SCD1 and SCD5 Modulate PARP-Dependent DNA Repair via Fatty Acid Desaturation in Glioblastoma

SCD1 and SCD5 Modulate PARP-Dependent DNA Repair via Fatty Acid Desaturation in Glioblastoma

  • bioRxiv. 2025 Jul 27:2025.07.23.666454. doi: 10.1101/2025.07.23.666454.
Hayk Mnatsakanyan 1 2,  Alessandro Sammarco 3,  Rami Awwad 1,  Abigail Hewett 1,  Elie Roumieh 1,  Caline Pechdimaljian 1,  Yana Azar 1,  Richa Pradhan 1,  Baolong Su 4 5,  Kevin J Williams 4 5,  Steven J Bensinger 3 4,  Christian E Badr 1 2
Affiliations

Affiliations

  • 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, CA, USA.
  • 4 UCLA Lipidomics Laboratory, University of California, Los Angeles, CA, USA.
  • 5 Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA.
PMID: 40777251 DOI: 10.1101/2025.07.23.666454
Abstract

Glioblastoma (GBM) relies on fatty acid metabolism to sustain its aggressive growth. While the role of stearoyl-CoA desaturase-1 (SCD1) in GBM is established, the function of its brain-enriched isoform, SCD5, remains unexplored. Here, we demonstrate that SCD5 is essential for glioblastoma stem cell (GSC) maintenance and genomic stability, with elevated expression in GSCs that declines upon differentiation, underscoring its role in tumor initiation. Through shotgun lipidomics, 13C metabolic flux analysis, and functional genomics, we reveal that SCD1 and SCD5 play non-redundant roles in fatty acid desaturation, with SCD5 preferentially desaturating C18:0 and uniquely contributing to sphingolipid remodeling. Genetic silencing of either isoform disrupts cell cycle progression, impairs DNA damage repair, and reduces GSC viability, while SCD5 knockdown significantly extends survival in orthotopic GBM models. 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 novel therapeutic strategy to eliminate therapy-resistant GSCs and enhance the efficacy of genotoxic or immunotherapeutic interventions.

Figures
Products