甲型流感病毒（IAV）是一种有包膜、负义、单链的RNA病毒，可在全球范围内造成大流行，导致较高的人类发病率和死亡率。由于抗原漂移、抗原转变及人畜共患等原因，导致甲型流感病毒的传播性、致病性不断发生改变，为防治工作带来持续挑战。

流感病毒感染会引起宿主细胞的代谢重编程，导致细胞中代谢物和代谢通路发生变化，从而为其复制提供能量和物质。但流感病毒如何引起代谢物和代谢通路发生变化，以及代谢物和代谢通路如何调控流感病毒复制，目前都未完全阐明。为了深入探索流感病毒感染与代谢物和代谢通路间的作用关系，我们以感染复数（MOI）为3的A/WSN/1933（WSN/H1N1）感染人非小细胞肺癌细胞（A549），12小时后收取细胞对其进行代谢组学和转录组学测序。本研究共筛选到101个上调的显著差异代谢物和108个下调的显著差异代谢物，对差异代谢物进行KEGG分析，发现碳水化合物代谢（糖代谢）、氨基酸代谢、脂代谢以及核苷酸代谢被富集到。通过MASE分析发现糖酵解和线粒体氧化中的代谢物浓度变化显著，因此我们将进一步研究糖酵解途径和线粒体氧化。通过代谢组学和转录组学联合分析发现，WSN感染激活HIF-1α信号通路，而HIF-1α信号通路与糖酵解具有关联性，糖酵解部分关键酶是HIF-1α信号通路的靶基因。有研究报道病毒感染后损伤线粒体，刺激线粒体产生大量活性氧（Mito-ROS），而Mito-ROS是HIF-1α的激活剂。

基于代谢组学和转录组学分析结果，我们构建了WSN感染的A549细胞和小鼠模型，深入研究Mito-ROS/HIF-1α-糖酵解轴在感染过程中对病毒复制的作用。结果发现WSN感染引发线粒体损伤，产生大量活性氧（mtROS），从而激活下游HIF-1α信号通路，导致葡萄糖转运体（Glut）、己糖激酶（HK2）以及乳酸脱氢酶（LDHA）的表达升高，最终促进葡萄糖摄取和糖酵解反应。另外，通过抑制A549细胞或小鼠体内的糖酵解、HIF-1α和ROS可有效缓解体外病毒的复制以及缓解感染WSN引起的损伤。综上，我们对WSN感染的A549细胞进行代谢组学分析以及代谢组学和转录组学的联合分析，在此基础上深入研究了Mito-ROS/HIF-1α-糖酵解轴在WSN感染过程中的调控作用以及分子机制，证实了Mito-ROS/HIF-1α -糖酵解轴在WSN感染过程中的分子机制，揭示了糖酵解作为抗流感病毒药物开发的潜在靶点。

甲型流感病毒（IAV）是一种有包膜、负义、单链的RNA病毒，可在全球范围内造成大流行，导致较高的人类发病率和死亡率。由于抗原漂移、抗原转变及人畜共患等原因，导致甲型流感病毒的传播性、致病性不断发生改变，为防治工作带来持续挑战。

流感病毒感染会引起宿主细胞的代谢重编程，导致细胞中代谢物和代谢通路发生变化，从而为其复制提供能量和物质。但流感病毒如何引起代谢物和代谢通路发生变化，以及代谢物和代谢通路如何调控流感病毒复制，目前都未完全阐明。为了深入探索流感病毒感染与代谢物和代谢通路间的作用关系，我们以感染复数（MOI）为3的A/WSN/1933（WSN/H1N1）感染人非小细胞肺癌细胞（A549），12小时后收取细胞对其进行代谢组学和转录组学测序。本研究共筛选到101个上调的显著差异代谢物和108个下调的显著差异代谢物，对差异代谢物进行KEGG分析，发现碳水化合物代谢（糖代谢）、氨基酸代谢、脂代谢以及核苷酸代谢被富集到。通过MASE分析发现糖酵解和线粒体氧化中的代谢物浓度变化显著，因此我们将进一步研究糖酵解途径和线粒体氧化。通过代谢组学和转录组学联合分析发现，WSN感染激活HIF-1α信号通路，而HIF-1α信号通路与糖酵解具有关联性，糖酵解部分关键酶是HIF-1α信号通路的靶基因。有研究报道病毒感染后损伤线粒体，刺激线粒体产生大量活性氧（Mito-ROS），而Mito-ROS是HIF-1α的激活剂。

基于代谢组学和转录组学分析结果，我们构建了WSN感染的A549细胞和小鼠模型，深入研究Mito-ROS/HIF-1α-糖酵解轴在感染过程中对病毒复制的作用。结果发现WSN感染引发线粒体损伤，产生大量活性氧（mtROS），从而激活下游HIF-1α信号通路，导致葡萄糖转运体（Glut）、己糖激酶（HK2）以及乳酸脱氢酶（LDHA）的表达升高，最终促进葡萄糖摄取和糖酵解反应。另外，通过抑制A549细胞或小鼠体内的糖酵解、HIF-1α和ROS可有效缓解体外病毒的复制以及缓解感染WSN引起的损伤。综上，我们对WSN感染的A549细胞进行代谢组学分析以及代谢组学和转录组学的联合分析，在此基础上深入研究了Mito-ROS/HIF-1α-糖酵解轴在WSN感染过程中的调控作用以及分子机制，证实了Mito-ROS/HIF-1α -糖酵解轴在WSN感染过程中的分子机制，揭示了糖酵解作为抗流感病毒药物开发的潜在靶点。

Influenza A virus (IAV) is a negative-sense, single-stranded RNA virus enclosed in an envelope, capable of causing global pandemics with significant human morbidity and mortality rates. The evolving nature of influenza A virus, driven by antigenic drift, antigenic shift, and zoonotic transmission, presents ongoing challenges for prevention and control strategies.

Infection with the influenza virus can induce metabolic alterations in host cells, resulting in changes in metabolites and metabolic pathways that facilitate viral replication by providing necessary energy and materials. However, the precise mechanisms through which the influenza virus modulates metabolites and metabolic pathways, as well as how these components influence viral replication, remain incompletely understood. To delve deeper into the interplay between influenza virus infection and cellular metabolism, human lung epithelial cells (A549) were infected with A/WSN/1933 (WSN/H1N1) at a multiplicity of infection (MOI) of 3, and cell samples were collected 12 hours post-infection for metabolomic and transcriptomic sequencing. The analysis identified 101 significantly upregulated and 108 significantly downregulated differential metabolites. KEGG analysis of these metabolites revealed enrichment in carbohydrate metabolism (glycolysis), amino acid metabolism, lipid metabolism, and nucleotide metabolism. Notably, MASE analysis indicated notable alterations in metabolite concentrations within glycolysis and mitochondrial oxidation pathways, prompting further investigation into these areas. Integrated metabolomic and transcriptomic analysis unveiled that WSN infection triggers the HIF-1α signaling pathway, linked to glycolysis, with key glycolysis enzymes being target genes of this pathway. Viral infection was found to impair mitochondria, leading to increased production of reactive oxygen species (Mito-ROS) within mitochondria, which in turn activates HIF-1α.

Utilizing metabolomics and transcriptomics analyses, we established A549 cell and mouse models infected with WSN to explore the involvement of the Mito-ROS/HIF-1α-glycolysis axis in viral replication during infection. Findings indicated that WSN infection induced mitochondrial impairment, leading to heightened reactive oxygen species (mtROS) production, which in turn activated the downstream HIF-1α signaling cascade. This activation resulted in elevated expression levels of glucose transporter (Glut), hexokinase 2 (HK2), and lactate dehydrogenase A (LDHA), consequently enhancing glucose uptake and glycolytic activity. Notably, inhibition of glycolysis, HIF-1α, and ROS in A549 cells or mice effectively attenuated viral replication in vitro and mitigated WSN-induced damage. In summary, our study integrated metabolomics analysis of WSN-infected A549 cells with transcriptomics analysis to elucidate the regulatory function of the Mito-ROS/HIF-1α-glycolysis axis in WSN infection, unveiling the underlying molecular mechanisms of viral infection. The investigation substantiated the molecular underpinnings of the Mito-ROS/HIF-1α-glycolysis axis in WSN infection and identified glycolysis as a prospective target for the advancement of antiviral interventions against influenza viruses.

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