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<p>The recent outbreaks of mpox and other poxvirus diseases worldwide have highlighted the critical need for effective antiviral treatments. Throughout its life cycle, MPXV, a member of the <i>Orthopoxvirus</i> genus, takes advantage of the host’s lipid metabolism. In addition to being essential for maintaining cellular homeostasis, lipids are also used by viruses for entrance, reproduction, assembly, and egress. Lipid rafts (LRs), membrane microdomains rich in cholesterol that are essential for viral entry and viral envelope structure, are a crucial component of this exploitation. This study summarizes evidence that MPXV uses lipid signaling, metabolism, and compartmentalization, with an emphasis on cholesterol-rich LRs as crucial life-cycle platforms. We use analogies from related poxviruses to assess our current understanding of these lipid-centric processes comprehensively. The possibility for repurposing lipid-lowering medications, such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as adjuvant antiviral therapy is another significant translational consequence highlighted in the paper. These medications provide a viable, host-directed approach to supplement current direct antivirals by interfering with host lipid pathways required by MPXV. We review the current preclinical data, the mechanistic rationale, and key issues for further study of this treatment strategy.</p> Graphical abstract <p>MPXV life cycle phases that are lipid-dependent and the therapeutic focus of lipid-lowering medications. The main hypothesis, that host lipids are necessary for MPXV replication and that lipid-lowering medications are potential adjuvant treatments, is shown in this graphic. MPXV requires cholesterol-rich LRs for macropinocytosis, enabling it to enter host cells after attachment. Membrane-bound cytoplasmic factories are the site of viral replication, and host-derived phospholipids and cholesterol are incorporated into virion assembly. To create enveloped virions that aid viral dissemination, a fraction of virions acquires additional membranes from the cholesterol-rich Golgi and endosomal compartments. Statins, fibrates, PCSK9 inhibitors, and bile acid sequestrants are examples of lipid-lowering medications that prevent the manufacture or absorption of cholesterol. The suppression of LDL-derived cholesterol transport from lysosomes and late endosomes to the endoplasmic reticulum is a significant downstream impact that interferes with the cholesterol supply necessary for membrane synthesis and viral replication factory biogenesis. Crucially, although these processes are well established in vaccinia virus, they have not been extensively studied in MPXV and require direct experimental confirmation.</p>

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Cellular lipids: fundamental host factors for monkeypox virus replication and pathogenesis

  • 期刊论文

  • 发表日期：

    2026年3月18日

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  • Mohammed S. Nawrooz,
  • Waam Mohammed Taher,
  • Mariem Alwan,
  • Mahmood Jawad,
  • Hiba Mushtaq,
  • Omer Qutaiba B. Allela

摘要

The recent outbreaks of mpox and other poxvirus diseases worldwide have highlighted the critical need for effective antiviral treatments. Throughout its life cycle, MPXV, a member of the Orthopoxvirus genus, takes advantage of the host’s lipid metabolism. In addition to being essential for maintaining cellular homeostasis, lipids are also used by viruses for entrance, reproduction, assembly, and egress. Lipid rafts (LRs), membrane microdomains rich in cholesterol that are essential for viral entry and viral envelope structure, are a crucial component of this exploitation. This study summarizes evidence that MPXV uses lipid signaling, metabolism, and compartmentalization, with an emphasis on cholesterol-rich LRs as crucial life-cycle platforms. We use analogies from related poxviruses to assess our current understanding of these lipid-centric processes comprehensively. The possibility for repurposing lipid-lowering medications, such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as adjuvant antiviral therapy is another significant translational consequence highlighted in the paper. These medications provide a viable, host-directed approach to supplement current direct antivirals by interfering with host lipid pathways required by MPXV. We review the current preclinical data, the mechanistic rationale, and key issues for further study of this treatment strategy.

Graphical abstract

MPXV life cycle phases that are lipid-dependent and the therapeutic focus of lipid-lowering medications. The main hypothesis, that host lipids are necessary for MPXV replication and that lipid-lowering medications are potential adjuvant treatments, is shown in this graphic. MPXV requires cholesterol-rich LRs for macropinocytosis, enabling it to enter host cells after attachment. Membrane-bound cytoplasmic factories are the site of viral replication, and host-derived phospholipids and cholesterol are incorporated into virion assembly. To create enveloped virions that aid viral dissemination, a fraction of virions acquires additional membranes from the cholesterol-rich Golgi and endosomal compartments. Statins, fibrates, PCSK9 inhibitors, and bile acid sequestrants are examples of lipid-lowering medications that prevent the manufacture or absorption of cholesterol. The suppression of LDL-derived cholesterol transport from lysosomes and late endosomes to the endoplasmic reticulum is a significant downstream impact that interferes with the cholesterol supply necessary for membrane synthesis and viral replication factory biogenesis. Crucially, although these processes are well established in vaccinia virus, they have not been extensively studied in MPXV and require direct experimental confirmation.