Authors
Kim Chi Thi Vu, Yvonne F Grande, Laura Bierau, Martin Schauflinger, Emilia Spremberg, Joanne Wei Kay Ku, Julia Hehner, Anja Schöbel, Eva Herker
Published in
Cell death & disease. Volume 17. Issue 1. Jul 08, 2026. Epub Jul 08, 2026.
Abstract
Orthoflavivirus infection is intricately linked to host cell lipid metabolism, yet the function of bioactive lipids as regulators of infection remains to be elucidated. Here, we investigated the role of lipid mediator pathways, namely ALOX/COX enzymes and upstream lipases, in orthoflavivirus replication by comparing dengue virus (DENV), Zika virus (ZIKV), wild-type yellow fever virus (YFV-Asibi), and the live-attenuated vaccine strain YFV-17D. DENV, ZIKV, and YFV-Asibi, but not the vaccine strain, induced COX2 expression in Huh7 hepatoma cells, correlating with prostaglandin E2 (PGE2) levels in culture supernatants. All four viruses replicated more efficiently in COX2-, ALOX15-, and MGLL-deficient cells, indicating a broadly antiviral role for these enzymes. In contrast, DENV and ZIKV specifically induced ALOX12 expression and depended on ALOX12 for efficient viral RNA replication, as demonstrated by reduced genome copy numbers, altered dsRNA replication compartment morphology, and decreased infectious titers in ALOX12-depleted cells. Direct measurement of lipid peroxidation revealed that ZIKV infection markedly elevated lipid peroxide levels through both ALOX12-dependent and -independent mechanisms, whereas DENV infection did not cause detectable lipid peroxide accumulation. Consistent with this, the ferroptosis inhibitor ferrostatin impaired DENV replication, while the ferroptosis inducer erastin enhanced it; this proviral effect of erastin was fully abolished by ALOX12 knockdown, indicating that DENV depends entirely on ALOX12-driven lipid peroxidation. Iron chelation reduced both DENV and ZIKV infection, confirming a requirement for iron-dependent oxidative processes. The proviral role of lipid peroxidation extended beyond hepatoma cells, as ferrostatin treatment significantly reduced DENV and ZIKV infection in human microglia cells. Our results reveal virus-specific exploitation of lipid peroxidation pathways by orthoflaviviruses and identify ALOX12-dependent lipid peroxidation as a novel proviral mechanism that may represent a target for antiviral intervention.
PMID:
42420242
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.
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