pORF3-driven biogenesis of lipid droplets facilitates HEV infectivity

Lipid droplets (LDs) are dynamic organelles that mediate lipid metabolism and various cellular processes. However, the interplay between hepatocyte LDs and hepatitis E remains poorly understood. Using targeted lipidomics and lipid profiling in rodent models, we reveal that hepatitis E virus (HEV) infection substantially increases hepatic LD biogenesis. Mechanistically, HEV pORF3 is a key LD biogenesis inducer and an essential factor for viral infectivity in vivo. pORF3 undergoes liquid-liquid phase-separation to form condensates that associate with LD phospholipid monolayer peripherally to upregulate cholesterol anabolic pathways, thereby promoting triacylglycerol and cholesterol ester synthesis. Consistently, genetic loss of ORF3 or pharmacologic reduction of LD biogenesis with the statin atorvastatin substantially suppressed HEV infection in vivo. These findings identify LD biogenesis as a host dependency for HEV infectivity and propose alternative strategies for HEV intervention by targeting LD-directed metabolic pathways.

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Publication Details

Journal
Cell Reports
Published
2025-10-01
DOI
https://doi.org/10.1016/j.celrep.2025.116406
Citations
2
Primary Topic
Hepatitis Viruses Studies and Epidemiology
Type
article
Field-Weighted Citation Impact
2.64
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article

pORF3-driven biogenesis of lipid droplets facilitates HEV infectivity

Siddharth Sridhar, Yao‐Wei Huang, Pinglong Xu, Shengduo Liu et al.
2 citations
Cell Reports
Hepatitis Viruses Studies and Epidemiology
2.64
article

pORF3-driven biogenesis of lipid droplets facilitates HEV infectivity

Siddharth Sridhar, Yao‐Wei Huang, Pinglong Xu, Shengduo Liu, Cunqi Ye, Ling-Dong Xu, Yezhang Zhu, Qiming Sun, Xinyuan Yu, Dante Neculai, Qi Zhang, Fei Zhang, Mengdi Zhang, Li Shen, Chao Miao, Tingbo Liang
article en
2 citations

Abstract

Lipid droplets (LDs) are dynamic organelles that mediate lipid metabolism and various cellular processes. However, the interplay between hepatocyte LDs and hepatitis E remains poorly understood. Using targeted lipidomics and lipid profiling in rodent models, we reveal that hepatitis E virus (HEV) infection substantially increases hepatic LD biogenesis. Mechanistically, HEV pORF3 is a key LD biogenesis inducer and an essential factor for viral infectivity in vivo. pORF3 undergoes liquid-liquid phase-separation to form condensates that associate with LD phospholipid monolayer peripherally to upregulate cholesterol anabolic pathways, thereby promoting triacylglycerol and cholesterol ester synthesis. Consistently, genetic loss of ORF3 or pharmacologic reduction of LD biogenesis with the statin atorvastatin substantially suppressed HEV infection in vivo. These findings identify LD biogenesis as a host dependency for HEV infectivity and propose alternative strategies for HEV intervention by targeting LD-directed metabolic pathways.

Cell ReportsVol. 44(10)
South China Agricultural University (CN), Zhejiang Lab (CN), First Affiliated Hospital Zhejiang University (CN), Zhejiang University (CN), University of Hong Kong (HK)
Openalex Percentile: Top 8%
Hepatitis Viruses Studies and Epidemiology
2.64
DOIOpen Access PDFOpenAlex
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