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Article Open Access

Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes

  • Authors:
    • Jianping He
    • Chenxi Feng
    • Yaohan Xu
    • Yan Chen
    • Siji Chen
    • Jiang Zhu
    • Yinjing Song
    • Hao Cheng
  • View Affiliations / Copyright

    Affiliations: Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
    Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 316
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    Published online on: September 11, 2025
       https://doi.org/10.3892/mmr.2025.13681
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Abstract

Genital herpes (GH), which is primarily caused by herpes simplex virus type 2 (HSV‑2), is the leading cause of genital ulcers worldwide, and is characterized by recurring outbreaks of painful genital lesions. Despite the high prevalence of GH, the metabolic and transcriptomic mechanisms underlying disease recurrence remain poorly understood. Therefore, the present study aimed to identify metabolic alterations in patients with HSV‑2 GH via integrating transcriptomics, metabolomics and single‑cell RNA‑sequencing (scRNA‑seq) analyses. Non‑targeted metabolomics identified significant changes in pathways associated with glycerophospholipid metabolism, amino acid biosynthesis and cholesterol metabolism. In addition, RNA‑seq analysis revealed that genes associated with the alanine, aspartate and glutamate, and valine, leucine and isoleucine metabolism pathways were significantly upregulated in patients with recurrent HSV‑2 GH. Furthermore, scRNA‑seq data showed that IDH1 and ETNK1 were upregulated, mainly in dendritic cells (DCs), plasmacytoid DCs and monocytes derived from patients with GH. Notably, the expression levels of genes associated with oxidative phosphorylation, such as MT‑CYB and MT‑CO3, were significantly elevated across monocytes, T cells and B cells. Overall, the results of the current study suggested that metabolic reprogramming could occur in patients with recurrent HSV‑2 GH, thus providing potential biomarkers and therapeutic targets that could be involved in the future development of treatment approaches.
View Figures

Figure 1

Metabolomics analysis of blood
samples from patients with recurrent herpes simplex virus type 2
GH. (A) Volcano plot depicting differentially expressed metabolites
in the serum of patients with GH (n=14) vs. healthy controls
(n=14). Red dots represent significantly upregulated metabolites,
blue dots represent significantly downregulated metabolites; key
metabolites are labelled for reference. (B) Heatmap of the top15
metabolites up or downregulated in GH compared with healthy
controls. (C) KEGG enrichment scatter plot of the significantly
altered metabolites in the serum of patients with GH (n=14) vs.
healthy controls (n=14). (D) Heatmap of significantly altered
metabolites in glycerophospholipid, cholesterol and linoleic acid
metabolism pathways. FC, fold change; GH, genital herpes; KEGG,
Kyoto Encyclopedia of Genes and Genomes.

Figure 2

GSEA of metabolites in patients with
herpes simplex virus type 2 GH. (A) GSEA results of the metabolites
in the serum of patients with GH (n=14) vs. healthy controls
(n=14). GSEA enrichment in (B) biosynthesis of amino acids and (C)
neuroactive ligand-receptor interaction. (D) Heatmap showing
metabolites in neuroactive ligand-receptor interaction and
biosynthesis of amino acids and phenylpropanoids. GH, genital
herpes; GSEA, Gene Set Enrichment Analysis.

Figure 3

RNA-sequencing analysis of the
significant metabolic pathways in PBMCs from patients with
recurrent herpes simplex virus type 2 GH. (A) Volcano plot and (B)
heatmap showing DEGs related to glycerophospholipid metabolism in
the PBMCs of patients with GH (n=14) vs. healthy controls (n=14).
(C) Volcano plot and (D) heatmap showing DEGs related to
cholesterol metabolism in the PBMCs of patients with GH (n=14) vs.
healthy controls (n=14). (E) Volcano plot and (F) heatmap showing
DEGs related to biosynthesis of amino acids in the PBMCs of
patients with GH (n=14) vs. healthy controls (n=14). (G) Reverse
transcription-quantitative PCR analysis of the mRNA expression
levels of ETNK1, PLA2G4A, SOS1, GPD2, IDH1 and PSAT1
in the PBMCs of patients with GHP. P-values were determined by
unpaired Student's t-test: **P<0.01, ***P<0.001. DEGs,
differentially expressed genes; FC, fold change; GH, genital
herpes; PBMCs, peripheral blood mononuclear cells.

Figure 4

scRNA-seq analysis of the significant
metabolic pathway-associated genes in patients with recurrent
herpes simplex virus type 2 GH. (A) t-SNE of scRNA-seq data showing
clusters of cells in the PBMCs and neutrophils of patients with GH
(n=4) and healthy controls (n=4). (B) Dot plot of scRNA-seq data
showing key metabolite-associated genes in the clusters of cells in
the PBMCs and neutrophils of patients with GH (n=4) and healthy
controls (n=4). (C) Violin plots of scRNA-seq data showing key
metabolite-associated genes the clusters of cells in the PBMCs and
neutrophils of patients with GHP (n=4) and healthy controls (n=4).
GH, genital herpes; PBMCs, peripheral blood mononuclear cells;
scRNA-seq, single-cell RNA-sequencing; t-SNE, t-distributed
Stochastic Neighbor Embedding.

Figure 5

KEGG enrichment analysis of
metabolism-associated DEGs from RNA-seq data in patients with
recurrent herpes simplex virus type 2 GH. (A) Scatter plot of KEGG
enrichment showing metabolism-associated DEGs in metabolic pathways
from RNA-Seq data of the PBMC of GHP (n=14) and healthy controls
(n=14). Volcano plots showing DEGs in (B) carbon metabolism, (C)
alanine, aspartate and glutamate, (D) folate biosynthesis and (E)
valine, leucine and isoleucine degradation. DEGs, differentially
expressed genes; FC, fold change; GH, genital herpes; KEGG, Kyoto
Encyclopedia of Genes and Genomes; RNA-seq, RNA-sequencing.

Figure 6

KEGG enrichment analysis of
metabolism-associated DEGs from scRNA-seq data in patients with
recurrent herpes simplex virus type 2 GH. (A) Scatter plot of KEGG
enrichment analysis showing metabolism-associated DEGs, and (B) dot
plot of scRNA-seq data showing oxidate phosphorylation
pathway-associated DEGs in monocytes from the PBMCs and neutrophils
of patients with GH (n=4) and healthy controls (n=4). (C) Scatter
plot of KEGG enrichment analysis showing metabolism-associated
DEGs, and (D) dot plot of scRNA-seq data showing oxidate
phosphorylation pathway-associated DEGs in dendritic cells. (E)
Scatter plot of KEGG enrichment analysis showing
metabolism-associated DEGs, and (F) dot plot of scRNA-seq data
showing oxidate phosphorylation pathway-associated DEGs in T cells.
(G) Scatter plot of KEGG enrichment analysis showing
metabolism-associated DEGs, and (H) dot plot of scRNA-seq data
showing oxidate phosphorylation pathway-associated DEGs in B cells.
DEGs, differentially expressed genes; H, genital herpes; KEGG,
Kyoto Encyclopedia of Genes and Genomes; scRNA-seq, single-cell
RNA-sequencing.
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He J, Feng C, Xu Y, Chen Y, Chen S, Zhu J, Song Y and Cheng H: Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes. Mol Med Rep 32: 316, 2025.
APA
He, J., Feng, C., Xu, Y., Chen, Y., Chen, S., Zhu, J. ... Cheng, H. (2025). Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes. Molecular Medicine Reports, 32, 316. https://doi.org/10.3892/mmr.2025.13681
MLA
He, J., Feng, C., Xu, Y., Chen, Y., Chen, S., Zhu, J., Song, Y., Cheng, H."Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes". Molecular Medicine Reports 32.6 (2025): 316.
Chicago
He, J., Feng, C., Xu, Y., Chen, Y., Chen, S., Zhu, J., Song, Y., Cheng, H."Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes". Molecular Medicine Reports 32, no. 6 (2025): 316. https://doi.org/10.3892/mmr.2025.13681
Copy and paste a formatted citation
x
Spandidos Publications style
He J, Feng C, Xu Y, Chen Y, Chen S, Zhu J, Song Y and Cheng H: Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes. Mol Med Rep 32: 316, 2025.
APA
He, J., Feng, C., Xu, Y., Chen, Y., Chen, S., Zhu, J. ... Cheng, H. (2025). Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes. Molecular Medicine Reports, 32, 316. https://doi.org/10.3892/mmr.2025.13681
MLA
He, J., Feng, C., Xu, Y., Chen, Y., Chen, S., Zhu, J., Song, Y., Cheng, H."Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes". Molecular Medicine Reports 32.6 (2025): 316.
Chicago
He, J., Feng, C., Xu, Y., Chen, Y., Chen, S., Zhu, J., Song, Y., Cheng, H."Integrated metabolomics and transcriptomics analyses reveal changes in metabolites and their associated gene expression in the blood of patients with recurrent HSV‑2 genital herpes". Molecular Medicine Reports 32, no. 6 (2025): 316. https://doi.org/10.3892/mmr.2025.13681
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