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. 2025 Jul 24;20(7):e0327101.
doi: 10.1371/journal.pone.0327101. eCollection 2025.

Comprehensive characterization of the competitive endogenous RNA network revealing its immune-related functions in hepatic ischemia-reperfusion injury

Lirong Liu  1 , Qi Wang  1 , Shuang Qin  1 , Chang Su  1 , Xin Hai  1 , Zhenkuan Yuan  1
Affiliations

Comprehensive characterization of the competitive endogenous RNA network revealing its immune-related functions in hepatic ischemia-reperfusion injury

Lirong Liu et al. PLoS One. .

Abstract

Hepatic ischemia-reperfusion injury (HIRI) is a common complication in liver surgery and transplantation. Recent studies have revealed the significant role of the competing endogenous RNA (ceRNA) network in HIRI. Herein, we comprehensively analyzed the HIRI-related ceRNA network and its correlation with immune-related pathways and immune cells in HIRI patients. We identified 449 lncRNAs, 26 miRNAs, and 548 mRNAs differentially expressed in HIRI patients. We constructed a HIRI-related ceRNA network in liver transplant patients consisting of 3 lncRNAs, 3 miRNAs, and 29 mRNAs. Biological function analysis showed that the HIRI-related ceRNA network contributes to HIRI progression by regulating calcium ion-related regulatory pathways and processes. An immune-related ceRNA subnetwork, which consists of 1 lncRNA (PARD6G-AS1), 1 miRNA (hsa-miRNA-125b-5p), and 4 mRNAs (PLAU, CCR5, FGF5 and IL24) was obtained. The immune-related ceRNA subnetwork was significantly related to the immune-related pathways and immune cell infiltration. The PARD6G-AS1/miR-125b-5p/IL24 axis was identified as a potential ceRNA sponge that may influence NK cell activity in HIRI. Our results underlined that the lncRNA-miRNA-mRNA ceRNA network can positively or negatively regulate immune-related functions and infiltrating immune cells mediated HIRI, which could provide further insight into novel molecular therapeutic targets.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig 1
Fig 1. Flowchart of this study.
Fig 2
Fig 2. Identification of significant expression changes in RNAs after liver transplant.
A-C. Volcano plot for the DElncRNAs, DEmiRNAs and DEmRNAs in GSE151648. The black dots and green represent genes that are not significantly differentially expressed between IRI+ samples and IRI- samples, and the red dots on the left represent the downregulated genes and on the right represent upregulated genes in IRI+ samples. D-F. Heatmap of the DElncRNAs, DEmiRNAs and DEmRNAs in GSE151648. Genes expressed at high levels are shown in red, and genes expressed at low levels are shown in green.
Fig 3
Fig 3. Functional enrichment analysis of 548 mRNAs.
A. Bar graph of enriched terms across input gene lists colored by P values. B. Network of enriched terms colored by cluster ID, where nodes that share the same cluster ID are typically close to each other C. Network of enriched terms colored by P value, where terms containing more genes tend to have a more significant P value.
Fig 4
Fig 4. The functional annotation and protein-protein interaction (PPI) analysis of upmRNAs in the ceRNA network.
A. ceRNA network constructed by upmRNAs, downmiRNAs, and uplncRNAs. B. The top 10 significantly enriched BP biological process and relevant genes. C. The significantly enriched MF biological process and relevant genes. D. PPI network of upmRNAs in the ceRNA network. E. Cluster analyzed by the MCODE in the whole PPI network.
Fig 5
Fig 5. Correlation Analysis of RNA in ceRNA with immune pathways and immune cells, as well as the construction of ceRNA subnetwork.
A-C. Lollipop chart showing the relationship between miRNAs in ceRNA and immune pathways. D-F. Bar Chart showing the relationship between lncRNAs in ceRNA and immune pathways. G. The relationship between lncRNAs in ceRNA and immune cells(P < 0.05). H. Venn diagram showing the Intersecting genes between mRNAs in ceRNA and known immune genes. I. ceRNA subnetwork constructed based on immune-related RNAs in ceRNA, the yellow node represents lncRNA, the pink node represents miRNA and the blue nodes represent mRNA, and the edges among mRNA are their PPI interactions.
Fig 6
Fig 6. Validation of members of ceRNA subnetwork and immune relevance.
A. Spearman analysis of different infiltrating cells and B. the relationships between different tumor-infiltrating cells and members of the ceRNA subnetwork in liver biopsies. C. Showing the relationship between infiltrating immune cells and IL24, D. PLAU, and E. CCR5. F. Further illustrates the exact relationship between FGF5 and CD8 T cells, G. lncRNA PARD6G-AS1 and Monocytes, and F. miRNA has-miR-125b-5p and activated NK cells.
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