2. Academic Validation
  3. Fatty acid channelling into triglycerides and oxylipins drives ferroptosis resistance during oncogenic BRAF-induced senescence

Fatty acid channelling into triglycerides and oxylipins drives ferroptosis resistance during oncogenic BRAF-induced senescence

  • Cell Death Differ. 2026 May 26. doi: 10.1038/s41418-026-01766-x.
Markus S Hess # 1 2,  Kamal M Al-Shami # 1 2,  Carolina Dehesa Caballero 1 2,  Julie Haenlin 1 2,  Adriano B Chaves-Filho 1 3,  Lisa Schlicker 1 4,  Philipp Poeller 1 2,  Felix C E Vogel 1,  Ioanna Koltsaki 1,  Deniz Gedik 1,  Marta Campos Alonso 1,  Susanne Walz 5,  Carsten P Ade 6,  Martin Eilers 6,  Beate K Straub 7,  Jochen S Utikal 8 9 10,  Svenja Meierjohann 11,  Mathias T Rosenfeldt 11,  Marteinn T Snaebjornsson 1,  Almut Schulze 12
Affiliations

Affiliations

  • 1 Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 2 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 3 Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil.
  • 4 Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg.
  • 5 Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
  • 6 Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, Am Hubland, Würzburg, Germany.
  • 7 Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • 8 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 9 Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
  • 10 DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Heidelberg, Germany.
  • 11 Institute of Pathology, Julius Maximilians University and Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany.
  • 12 Division of Tumor Metabolism and Microenvironment, German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
  • # Contributed equally.
PMID: 42191968 DOI: 10.1038/s41418-026-01766-x
Abstract

Oncogene-induced senescence (OIS), a cellular programme initiated by activation of oncogenic signalling, provides a barrier to transformation and is accompanied by major reprogramming of cellular metabolism. We show here that induction of OIS by BRAFV600E expression in human diploid fibroblasts led to global changes in the cellular lipidome, characterised by a strong increase in triglycerides (TG) and a marked reduction in membrane phosphoglycerides carrying polyunsaturated fatty acids (PUFA) in their acyl-chains. Induction of BRAFV600E OIS resulted in a marked resistance towards lipid peroxidation and Ferroptosis. Inhibition of TG synthesis by blocking diacylglycerol O-acyltransferase 1 (DGAT1) resulted in PUFA re-distribution to membrane lipids and increased Ferroptosis sensitivity of senescent cells. Inhibition of DGAT also altered the senescence-associated secretory phenotype (SASP) and enhanced the secretion of oxylipins by BRAFV600E OIS cells. Combined blockade of DGAT1-dependent TG and COX2-dependent oxylipin synthesis fully restored Ferroptosis sensitivity in BRAFV600E OIS cells. Together, these findings indicate that channelling of PUFA towards TG synthesis confers protection from oxidative stress and Ferroptosis during BRAFV600E OIS but also limits the production of pro-inflammatory lipid mediators, a key feature of the senescent phenotype.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-129457
    98.0%, Ferroptosis Inducer