A diet enriched in highly poly-unsaturated fatty acids alters immune cell lipid composition and ferroptosis susceptibility
- 1Baker Heat and Diabetes Institute
Abstract
Ferroptosis is a regulated form of cell death that is dependent upon the peroxidation of phospholipids containing poly-unsaturated fatty acids (PL-PUFAs), particularly those with 4 or more double bonds. PL-PUFA content is dramatically different between immune cell types which directly influences their sensitivity to ferroptosis. Modulating the PL-PUFA content of various cells is becoming an attractive approach to increase the efficacy of therapies designed to target ferroptosis. In this study we aimed to determine whether a diet enriched in highly unsaturated PUFAs alters immune cell lipid composition and, consequently, the susceptibility to ferroptosis. To address this, mice were fed either a diet enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (High PUFA diet) or a standard control diet (Control diet) for eight weeks. Immune cells were then isolated from the bone marrow, blood, and lymph nodes for lipidomic analysis and sensitivity to ferroptosis. The High PUFA diet resulted in the widespread incorporation of EPA and DHA into multiple PL species across all immune cell types. However, the magnitude of incorporation differed between cell populations, with B cells exhibiting the greatest enrichment in PL-PUFA-EPA and PL-PUFA-DHA species, followed by monocytes and neutrophils, while T cells showed the lowest degree of enrichment. Importantly, these compositional changes were associated with increased susceptibility to ferroptosis in a cell and location specific manner. Collectively, these findings demonstrate that a diet enriched in highly unsaturated PUFAs increases PL-PUFAs in immune cells and broadly enhances immune cell susceptibility to ferroptosis. Therefore, altering dietary fatty acid composition may represent a strategy to influence ferroptosis sensitivity in conditions where either inducing or inhibiting ferroptosis is therapeutically desirable.
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BibTeX
@misc{morgan2026diet,
title = {{A diet enriched in highly poly-unsaturated fatty acids alters immune cell lipid composition and ferroptosis susceptibility}},
author = {P. K. Morgan and Y. Xu and T. J. C. Collins and C. Bertuzzo Veiga and N. A. Mellet and K. Huynh and P. Meikle and A. J. Murphy and G. I. Lancaster},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.20.760583},
url = {https://www.biorxiv.org/content/10.64898/2026.10.20.760583v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A diet enriched in highly poly-unsaturated fatty acids alters immune cell lipid composition and ferroptosis susceptibility
AU - P. K. Morgan
AU - Y. Xu
AU - T. J. C. Collins
AU - C. Bertuzzo Veiga
AU - N. A. Mellet
AU - K. Huynh
AU - P. Meikle
AU - A. J. Murphy
AU - G. I. Lancaster
PY - 2026
DA - 2026/10/20
PB - bioRxiv
DO - 10.64898/2026.10.20.760583
UR - https://www.biorxiv.org/content/10.64898/2026.10.20.760583v1
AB - Ferroptosis is a regulated form of cell death that is dependent upon the peroxidation of phospholipids containing poly-unsaturated fatty acids (PL-PUFAs), particularly those with 4 or more double bonds. PL-PUFA content is dramatically different between immune cell types which directly influences their sensitivity to ferroptosis. Modulating the PL-PUFA content of various cells is becoming an attractive approach to increase the efficacy of therapies designed to target ferroptosis. In this study we aimed to determine whether a diet enriched in highly unsaturated PUFAs alters immune cell lipid composition and, consequently, the susceptibility to ferroptosis. To address this, mice were fed either a diet enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (High PUFA diet) or a standard control diet (Control diet) for eight weeks. Immune cells were then isolated from the bone marrow, blood, and lymph nodes for lipidomic analysis and sensitivity to ferroptosis. The High PUFA diet resulted in the widespread incorporation of EPA and DHA into multiple PL species across all immune cell types. However, the magnitude of incorporation differed between cell populations, with B cells exhibiting the greatest enrichment in PL-PUFA-EPA and PL-PUFA-DHA species, followed by monocytes and neutrophils, while T cells showed the lowest degree of enrichment. Importantly, these compositional changes were associated with increased susceptibility to ferroptosis in a cell and location specific manner. Collectively, these findings demonstrate that a diet enriched in highly unsaturated PUFAs increases PL-PUFAs in immune cells and broadly enhances immune cell susceptibility to ferroptosis. Therefore, altering dietary fatty acid composition may represent a strategy to influence ferroptosis sensitivity in conditions where either inducing or inhibiting ferroptosis is therapeutically desirable.
ER -