Post by DKFZ German Cancer Research Center

How do senescent cells evade ferroptosis? Study in Cell Death & Differentiation from Almut Schulze's lab at #DKFZ points to triglyceride metabolism as the key. Cellular #senescence, the permanent growth arrest triggered by stress or oncogenic signalling, is a well-established barrier against uncontrolled cell proliferation. Yet when senescent cells accumulate in tissues over time, they promote #chronic #inflammation and can facilitate #tumour #development. Understanding how senescent cells survive and persist is therefore a central question in cancer and ageing research. A key challenge has been deciphering the #metabolic #changes that allow senescent cells to resist #cell #death, particularly #ferroptosis, a form of programmed cell death driven by lipid peroxidation. If senescent cells can be selectively eliminated, this could open new therapeutic avenues in #oncology and #age #related #disease. Researchers at DKFZ used fibroblasts with the BRAFV600E #oncogene (a mutation common in melanoma) to model oncogene-induced senescence (OIS) and map its lipid landscape. Their findings: 🔬 OIS cells showed a global remodelling of the lipidome: triglycerides increased markedly, while membrane phosphoglycerides carrying polyunsaturated fatty acids (PUFAs) were strongly reduced 🛡️ By channelling PUFAs away from cell membranes and into triglyceride storage, senescent cells rendered their membranes resistant to oxidative damage and thus to ferroptosis ⚙️ The enzyme DGAT1 was identified as central to this mechanism: its inhibition redistributed PUFAs back to membrane lipids and restored ferroptosis sensitivity 🔁 DGAT1 inhibition also altered the senescence-associated secretory phenotype (SASP), enhancing oxylipin secretion — pro-inflammatory lipid mediators ✅ Combined blockade of DGAT1-dependent triglyceride synthesis and COX2-dependent oxylipin production fully restored ferroptosis sensitivity in OIS cells The study illuminates how tightly lipid metabolism, inflammatory signalling, and cell survival are intertwined in senescent cells. The authors view these findings as a foundation for developing strategies to selectively eliminate senescent cells with potential implications for both #cancer #therapy and the treatment of age-related diseases. Congratulations to Markus Heß, Kamal Al-Shami, Carolina Dehesa Caballero, Julie Haenlin, Adriano Chaves-Filho, Lisa Schlicker, Philipp Poeller, Felix C. E. Vogel, Ioanna Koltsaki, Deniz Gedik, Marta Campos Alonso, Jochen Sven Utikal, Marteinn Snaebjornsson, Almut Schulze and all co-authors. Image: iStock Photo /mg