Magdalena Murray

All Publications

• Cell size modulates ferroptosis susceptibility. eLife Zatulovskiy, E., Murray, M. B., Zhang, S., Dixon, S. J., Skotheim, J. M. 2026; 15

  Abstract

  Size is a fundamental property of cells that influences many aspects of their physiology. This is because cell size sets the scale for all subcellular components and drives changes in the composition of the proteome. Given that large and small cells differ in their biochemical composition, we hypothesized that they should also differ in how they respond to signals and make decisions. Here, we investigated how cell size affects the susceptibility of human cells to cell death. We found that large cells are more resistant to ferroptosis caused by system xc- inhibition. Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of toxic lipid peroxides. This process is opposed by cysteine-dependent lipid peroxide detoxification mechanisms. We found that larger cells exhibit higher concentrations of the cysteine-containing metabolite glutathione and lower concentrations of membrane lipid peroxides. Mechanistically, this can be explained by the fact that larger cells had lower concentrations of an enzyme that enriches cellular membranes with peroxidation-prone polyunsaturated fatty acids, ACSL4, and increased concentrations of the glutathione-producing enzymes glutamate-cysteine ligase and glutathione synthetase, the iron-chelating protein ferritin, and the lysosomal protease cathepsin B, which can catabolize cysteine-rich extracellular proteins to produce additional cystine for fueling the synthesis of glutathione. Taken together, our results highlight the significant impact of cell size on cellular function and survival, revealing a size-dependent vulnerability to ferroptosis that could influence therapeutic strategies based on this cell death pathway.

  View details for DOI 10.7554/eLife.111544

  View details for PubMedID 42267631

  View details for PubMedCentralID PMC13252968

• Dissecting Complex Interactions Between Ferroptosis and the Proteasome. bioRxiv : the preprint server for biology Murray, M. B., Upadhyay, R., Szylo, K., Gautam, A., Goncalves, J., Forcina, G., Vinayak, A., Brandmann, O., Dixon, S. J. 2026

  Abstract

  The proteasome is an essential multiprotein complex whose inhibition can lead to apoptosis. Ferroptosis is a non-apoptotic cell death mechanism whose fundamental regulation continues to be elucidated. How proteasome function regulates ferroptosis sensitivity is poorly understood and difficult to study given the essential nature of the proteasome. Here, we isolated the effects of proteasome inhibition on ferroptosis by combining direct cell death imaging, cell death pathway-specific inhibitors, and mathematical modeling. We find that proteasome inhibition enhances sensitivity to ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition while simultaneously promoting resistance to ferroptosis induced by system xc - inhibition. Sensitization to GPX4 inhibition requires protein synthesis but not the apoptosis execution machinery and is opposed by the activating transcription factor 4 (ATF4) stress response pathway. This work demonstrates a complex role for proteasome function in ferroptosis regulation and establishes new methods to dissect cross-talk between ferroptosis and essential cellular processes.

  View details for DOI 10.64898/2026.03.28.714855

  View details for PubMedID 41959534

  View details for PubMedCentralID PMC13060147

• Lipid Composition Alters Ferroptosis Sensitivity. Cancer research Park, V. S., Pope, L. E., Ingram, J. P., Alchemy, G. A., Purkal, J. J., Murray, M. B., Jin, S., Andino-Frydman, E. Y., Singh, S., Chen, A., Narayanan, P., Kongpachith, S., Phillips, D. C., Dixon, S. J., Popovic, R. 2025

  Abstract

  Ferroptosis is a regulated non-apoptotic cell death process characterized by iron-dependent lipid peroxidation. Peroxidation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) is necessary for the execution of ferroptosis. Glutathione peroxidase 4 (GPX4) suppresses ferroptosis by reducing lipid hydroperoxides to lipid alcohols. GPX4 may be a useful target for drug development, highlighting the need to identify factors that govern GPX4 inhibitor sensitivity. Here, we found that reduced GPX4 expression was sufficient to induce ferroptosis in multiple adherent (2D) cancer cell cultures. However, lower GPX4 protein levels did not consistently affect tumor xenograft growth in mice. Culturing cells as spheroids (3D) was sufficient to reduce sensitivity to pharmacological GPX4 inhibition. Mechanistically, growth in 3D versus 2D conditions upregulated expression of the monounsaturated fatty acid (MUFA) biosynthetic gene stearoyl-CoA desaturase (SCD), altering the ratio of MUFA-PLs to PUFA-PLs in a direction favoring ferroptosis resistance. Similar shifts in MUFA-PL to PUFA-PL ratios were observed in xenograft tumors. Thus, lipidome remodeling in 3D growth conditions and in vivo may limit GPX4 inhibitor efficacy.

  View details for DOI 10.1158/0008-5472.CAN-24-4207

  View details for PubMedID 40911781

• Ferroptosis regulation by Cap'n'collar family transcription factors. The Journal of biological chemistry Murray, M. B., Dixon, S. J. 2024: 107583

  Abstract

  Ferroptosis is an iron-dependent cell death mechanism that may be important to prevent tumor formation and useful as a target for new cancer therapies. Transcriptional networks play a crucial role in shaping ferroptosis sensitivity by regulating the expression of transporters, metabolic enzymes, and other proteins. The Cap'n'collar (CNC) protein nuclear factor erythroid 2 like 2 (NFE2L2, also known as NRF2) is a key regulator of ferroptosis in many cells and contexts. Emerging evidence indicates that the related CNC family members BTB and CNC homology 1 (BACH1) and nuclear factor erythroid 2 like 1 (NFE2L1) also have non-redundant roles in ferroptosis regulation. Here, we comprehensively review the role of CNC transcription factors in governing cellular sensitivity to ferroptosis. We describe how CNC family members regulate ferroptosis sensitivity through modulation of iron, lipid, and redox metabolism. We also use examples of ferroptosis regulation by CNC proteins to illustrate the flexible and highly context-dependent nature of the ferroptosis mechanism between cells and conditions.

  View details for DOI 10.1016/j.jbc.2024.107583

  View details for PubMedID 39025451

• Protocol for detection of ferroptosis in cultured cells. STAR protocols Murray, M. B., Leak, L. B., Lee, W. C., Dixon, S. J. 2023; 4 (3): 102457

  Abstract

  Mammalian cells can die by apoptosis or by one of several non-apoptotic mechanisms, such as ferroptosis. Here, we present a protocol to distinguish ferroptosis from other cell death mechanisms in cultured cells. We describe steps for seeding cells, administering mechanism-specific cell death inducers and inhibitors, and measuring cell death and viability. We then detail the use of molecular markers to verify mechanisms of cell death. This protocol can be used to identify and distinguish ferroptosis in 2D and 3D cultures. For complete details on the use and execution of this protocol, please refer to Ko, et al. (2019),1 Magtanong, et al. (2022),2 and Armenta, et al. (2022).3.

  View details for DOI 10.1016/j.xpro.2023.102457

  View details for PubMedID 37556320

• Ferroptosis regulation by the NGLY1/NFE2L1 pathway. Proceedings of the National Academy of Sciences of the United States of America Forcina, G. C., Pope, L., Murray, M., Dong, W., Abu-Remaileh, M., Bertozzi, C. R., Dixon, S. J. 2022; 119 (11): e2118646119

  Abstract

  SignificanceFerroptosis is an oxidative form of cell death whose biochemical regulation remains incompletely understood. Cap'n'collar (CNC) transcription factors including nuclear factor erythroid-2-related factor 1 (NFE2L1/NRF1) and NFE2L2/NRF2 can both regulate oxidative stress pathways but are each regulated in a distinct manner, and whether these two transcription factors can regulate ferroptosis independent of one another is unclear. We find that NFE2L1 can promote ferroptosis resistance, independent of NFE2L2, by maintaining the expression of glutathione peroxidase 4 (GPX4), a key protein that prevents lethal lipid peroxidation. NFE2L2 can also promote ferroptosis resistance but does so through a distinct mechanism that appears independent of GPX4 protein expression. These results suggest that NFE2L1 and NFE2L2 independently regulate ferroptosis.

  View details for DOI 10.1073/pnas.2118646119

  View details for PubMedID 35271393