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bioRxiv · 10.64898/2026.11.10.765664

Avian reovirus triggered ferroptosis, modulated lipid metabolism, and induced lipid droplet formation in infected cells, which was mediated in part by the p10/FAST protein

Liu, M.·Kehlbeck, D.·Egana-Labrin, S.·Brodrick, A.·Sun, L.·Jones, J.·Sunny, N.·Broadbent, A. J.
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Abstract

In this study, we evaluated how avian reovirus (ARV) affected lipid metabolism and lipid droplets (LDs) in cell culture. ARV infection of chicken LMH cells significantly increased the size and number of LDs, however, LDs did not co-localize with virus factories, and neither overexpression by treatment with fatty acids (FAs), nor inhibition by treatment with TOFA or DGAT inhibitors significantly affected ARV replication. Lipidomic analysis revealed that following infection, total cellular lipid content increased approximately 25-fold, phosphatidylcholine (PC) content increased from 23.5 to 57.9%, and the polyunsaturated FA:monounsaturated FA ratio (PUFA:MUFA) decreased in membrane phospholipids but increased in triglycerides. Transcriptomic analysis revealed that there was also a reduction in the expression of genes involved in PUFA synthesis. As membrane PUFAs are susceptible to peroxidation, we investigated whether ARV induced ferroptosis. Consistent with this, ARV led to an increase in oxidative stress and lipid peroxidation that was partially iron dependent, and we found evidence that ferroptosis was proviral. Moreover, as ARV is known to form syncytia, we hypothesized that our observations were also the result of plasma membrane remodeling. Consistent with this, cells transfected with the ARV fusogenic p10/FAST protein formed syncytia, had a significantly upregulated number of LDs, and displayed hallmarks of ferroptosis. Taken together, we hypothesize that ARV induces syncytium formation and ferroptosis to facilitate viral spread to neighboring cells, but to prevent premature cell death due to these processes, lipid metabolism is modulated by infection, leading to an increase in LDs.

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Liu, M., Kehlbeck, D., Egana-Labrin, S., Brodrick, A., Sun, L., Jones, J., Sunny, N., Broadbent, A. J.. 2026-11-11. Avian reovirus triggered ferroptosis, modulated lipid metabolism, and induced lipid droplet formation in infected cells, which was mediated in part by the p10/FAST protein. https://doi.org/10.64898/2026.11.10.765664

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