Uridine, a Therapeutic Nucleoside, Exacerbates Alcoholic Liver Disease via SRC Kinase Activation: A Network Toxicology and Molecular Dynamics Perspective
Abstract
1. Introduction
2. Results
2.1. Screening of 1400 Exposure Variables
2.2. Further Screening of 33 Exposure Variables
2.3. In-Depth Exploration of Uridine’s Potential Target Identification in ALD
2.4. Construction of the PPI Network and Identification of Hub Gene Connectivity
2.5. KEGG and GO Enrichment Analyses
2.6. Single-Cell Profiling Reveals Immune–Fibrotic Dysregulation in ALD
2.7. Molecular Docking Analysis of Uridine with Core Target Proteins Associated with ALD
2.8. Molecular Dynamics Simulation Analysis
3. Discussion
3.1. Mendelian Randomization Analysis
3.2. Network Toxicology and Molecular Docking: Analysis of Multi-Target Synergistic Effects
3.3. Single-Cell Transcriptomics: Cellular Heterogeneity and Microenvironmental Localization of Target Genes
3.4. MD: Analyzing Binding Stability and Allosteric Regulation from Atomic Motion
3.5. Innovations and Limitations of This Study
4. Materials and Methods
4.1. Causal Effect Analysis of 1091 Blood Metabolites, 309 Metabolite Ratios, and ALD
4.2. Screening of Exposure Factors from the Results of Section 4.1
4.3. Acquisition of Uridine Targets
4.4. Collection of AD-Related Targets
4.5. Construction of Protein–Protein Interaction Network and Selection of Hub Targets
4.6. Functional and Pathway Enrichment Analysis of Target Genes
4.7. Single-Cell RNA Analysis of Hub Genes in ALD
4.8. Molecular Docking Interactions Between Hub Targets and Uridine
4.9. Molecular Dynamics Simulation
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AKT | Protein kinase B |
ALD | Alcoholic liver disease |
AMPK | AMP-activated protein kinase |
ADRB2 | Adrenergic receptor beta 2 |
AMBER | AMBER force field |
cGMP-PKG | Cyclic GMP-dependent protein kinase G |
CDA | Cedazuridine |
CNS | Central nervous system |
CHARMM | CHARMM force field |
CIs | Confidence intervals |
CytoHubba | Cytoscape plugin for hub gene identification |
DFG | Asp-Phe-Gly motif |
DisGeNET | Disease Gene Network |
EDTA | Ethylenediaminetetraacetic acid |
FAD | Flavin adenine dinucleotide |
FEL | Free energy landscape |
FYN | Fyn kinase |
GEO | Gene Expression Omnibus |
GPCR | G protein-coupled receptor |
GSK3B | Glycogen synthase kinase 3 beta |
GWAS | Genome-wide association study |
IVW | Inverse variance weighted |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
LD | Linkage disequilibrium |
LYN | Lyn kinase |
MD | Molecular dynamics |
MR | Mendelian randomization |
MR-Egger | MR-Egger regression |
MCODE | Molecular complex detection |
OR | Odds ratio |
PDB | Protein Data Bank |
PPI | Protein–protein interaction |
PC | Principal component |
RESP | RESPA multi-time step algorithm |
ROS | Reactive oxygen species |
SESN2 | Sestrin 2 |
SPC | Simple Point Charge water model |
SRC | Src kinase |
STAT3 | Signal Transducer and Activator of Transcription 3 |
THBS1 | Thrombospondin 1 |
TIM-3 | T cell immunoglobulin and mucin domain-containing molecule 3 |
TTD | Therapeutic Target Database |
UPP1 | Uridine Pyrophosphatase 1 |
UTP | Uridine Triphosphate |
UDP-GlCNAC | Uridine Diphosphate-N-acetylglucosamine |
VOM(bpy)2Cl | Vanadium complex [VO(bpy)2Cl] |
PD-1 | Programmed cell death protein 1 |
Rg | Radius of gyration |
SASA | Solvent-accessible surface area |
t-SNE | t-Distributed Stochastic Neighbor Embedding |
RMSD | Root Mean Square Deviation |
Appendix A
id.Exposure | Trait | nsnp | Method | pval | OR(95% CI) |
---|---|---|---|---|---|
GCST90199631 | 3-methyl-2-oxovalerate levels | 15 | Inverse variance weighted | 0.037 | 1.400 (1.021 to 1.919) |
GCST90199662 | Isovalerate (i5:0) levels | 17 | Inverse variance weighted | <0.001 | 1.513 (1.185 to 1.933) |
GCST90199738 | Stachydrine levels | 24 | Inverse variance weighted | 0.031 | 1.279 (1.023 to 1.600) |
GCST90199751 | Gamma-glutamylmethionine levels | 26 | Inverse variance weighted | 0.022 | 1.256 (1.034 to 1.526) |
GCST90199789 | 2-palmitoyl-GPC (16:0) levels | 16 | Inverse variance weighted | 0.03 | 1.319 (1.028 to 1.692) |
GCST90199796 | Docosapentaenoate (n6 DPA; 22:5n6) levels | 16 | Inverse variance weighted | 0.039 | 1.315 (1.014 to 1.707) |
GCST90199815 | 1-ribosyl-imidazoleacetate levels | 15 | Inverse variance weighted | 0.029 | 1.352 (1.031 to 1.773) |
GCST90199899 | 1-(1-enyl-palmitoyl)-GPC (p-16:0) levels | 25 | Inverse variance weighted | 0.038 | 1.254 (1.013 to 1.552) |
GCST90199944 | Indolin-2-one levels | 17 | Inverse variance weighted | 0.011 | 1.266 (1.055 to 1.519) |
GCST90199988 | Tyramine O-sulfate levels | 21 | Inverse variance weighted | 0.011 | 1.322 (1.067 to 1.638) |
GCST90200114 | Glycosyl-N-tricosanoyl-sphingadienine (d18:2/23:0) levels | 24 | Inverse variance weighted | 0.024 | 1.274 (1.033 to 1.571) |
GCST90200167 | Glutamine conjugate of C7H12O2 levels | 30 | Inverse variance weighted | 0.044 | 1.222 (1.006 to 1.485) |
GCST90200273 | 2-methoxyhydroquinone sulfate (2) levels | 22 | Inverse variance weighted | 0.047 | 1.163 (1.002 to 1.349) |
GCST90200277 | Bilirubin degradation product, C16H18N2O5 (1) levels | 23 | Inverse variance weighted | 0.018 | 1.166 (1.027 to 1.325) |
GCST90200378 | Cortisol levels (plasma) | 18 | Inverse variance weighted | 0.022 | 1.373 (1.047 to 1.800) |
GCST90200407 | Uridine levels | 18 | Inverse variance weighted | 0.019 | 1.300 (1.043 to 1.621) |
GCST90200470 | X-11470 levels | 33 | Inverse variance weighted | 0.002 | 1.285 (1.100 to 1.501) |
GCST90200518 | X-12839 levels | 27 | Inverse variance weighted | 0.043 | 1.169 (1.005 to 1.359) |
GCST90200629 | X-24337 levels | 28 | Inverse variance weighted | 0.004 | 1.260 (1.077 to 1.474) |
GCST90200660 | X-25957 levels | 20 | Inverse variance weighted | 0.049 | 1.278 (1.001 to 1.631) |
GCST90200679 | N-acetylarginine levels | 25 | Inverse variance weighted | 0.024 | 1.121 (1.015 to 1.237) |
GCST90200702 | Bilirubin degradation product, C17H18N2O4 (2) levels | 23 | Inverse variance weighted | 0.026 | 1.151 (1.017 to 1.302) |
GCST90200704 | Bilirubin (z,z) levels | 33 | Inverse variance weighted | 0.021 | 1.135 (1.019 to 1.265) |
GCST90200716 | Adenosine 5′-diphosphate (ADP) to phosphoethanolamine ratio | 23 | Inverse variance weighted | 0.008 | 1.243 (1.058 to 1.462) |
GCST90200823 | Adenosine 5′-diphosphate (ADP) to N-palmitoyl-sphingosine (d18:1 to 16:0) ratio | 22 | Inverse variance weighted | 0.031 | 1.150 (1.012 to 1.305) |
GCST90200843 | Adenosine 5′-monophosphate (AMP) to flavin adenine dinucleotide (FAD) ratio | 17 | Inverse variance weighted | 0.017 | 1.283 (1.046 to 1.574) |
GCST90200930 | Carnitine to acetylcarnitine (C2) ratio | 19 | Inverse variance weighted | 0.014 | 1.382 (1.069 to 1.786) |
GCST90200933 | Alpha-ketoglutarate to proline ratio | 24 | Inverse variance weighted | 0.037 | 1.279 (1.016 to 1.610) |
GCST90200940 | Adenosine 5′-diphosphate (ADP) to EDTA ratio | 25 | Inverse variance weighted | 0.003 | 1.271 (1.084 to 1.490) |
GCST90200958 | Adenosine 5′-diphosphate (ADP) to choline ratio | 20 | Inverse variance weighted | <0.001 | 1.367 (1.157 to 1.614) |
GCST90200962 | Adenosine 5′-diphosphate (ADP) to glutamine ratio | 19 | Inverse variance weighted | 0.003 | 1.320 (1.102 to 1.581) |
GCST90200969 | Adenosine 5′-monophosphate (AMP) to N-palmitoyl-sphingosine (d18:1 to 16:0) ratio | 23 | Inverse variance weighted | 0.01 | 1.316 (1.069 to 1.620) |
GCST90200980 | Phosphoethanolamine to choline ratio | 22 | Inverse variance weighted | 0.014 | 1.323 (1.058 to 1.653) |
Target Protein | Mode | Binding Energy (kcal/mol) | RMSD (l.b.) | RMSD (u.b.) |
---|---|---|---|---|
GSK3β | 1 | −6.2 | 0 | 0 |
GSK3β | 2 | −5.9 | 10.48 | 11.417 |
GSK3β | 3 | −5.7 | 10.587 | 12.213 |
GSK3β | 4 | −5.7 | 11.35 | 12.751 |
GSK3β | 5 | −5.6 | 2.094 | 2.739 |
GSK3β | 6 | −5.6 | 11.883 | 13.019 |
GSK3β | 7 | −5.6 | 10.464 | 12.336 |
GSK3β | 8 | −5.5 | 11.958 | 13.951 |
GSK3β | 9 | −5.5 | 10.536 | 12.283 |
FYN | 1 | −5.8 | 0 | 0 |
FYN | 2 | −5.5 | 4.445 | 8.273 |
FYN | 3 | −5.3 | 20.255 | 21.76 |
FYN | 4 | −5.3 | 19.685 | 21.447 |
FYN | 5 | −5.2 | 12.991 | 14.232 |
FYN | 6 | −5.1 | 16.306 | 18.021 |
FYN | 7 | −5.1 | 19.551 | 20.597 |
FYN | 8 | −5 | 15.97 | 17.596 |
FYN | 9 | −5 | 20.298 | 21.485 |
LYN | 1 | −4.9 | 0 | 0 |
LYN | 2 | −4.6 | 2.393 | 5.332 |
LYN | 3 | −4.6 | 1.791 | 5.382 |
LYN | 4 | −4.5 | 2.532 | 5.797 |
LYN | 5 | −4.4 | 2.914 | 4.5 |
LYN | 6 | −4.2 | 2.204 | 3.657 |
LYN | 7 | −4 | 2.433 | 4.414 |
LYN | 8 | −4 | 18.351 | 19.299 |
LYN | 9 | −4 | 2.281 | 5.179 |
SRC | 1 | −5.6 | 0 | 0 |
SRC | 2 | −5.2 | 2.119 | 2.344 |
SRC | 3 | −4.7 | 2.099 | 4.939 |
SRC | 4 | −4.7 | 2.351 | 4.883 |
SRC | 5 | −4.7 | 10.497 | 12.017 |
SRC | 6 | −4.7 | 2.225 | 5.673 |
SRC | 7 | −4.6 | 11.765 | 13.288 |
SRC | 8 | −4.6 | 11.315 | 12.514 |
SRC | 9 | −4.5 | 2.48 | 3.411 |
ADRB2 | 1 | −7.1 | 0 | 0 |
ADRB2 | 2 | −6.9 | 6.448 | 8.318 |
ADRB2 | 3 | −6.8 | 5.79 | 7.32 |
ADRB2 | 4 | −6.8 | 5.218 | 7.241 |
ADRB2 | 5 | −6.8 | 5.791 | 7.899 |
ADRB2 | 6 | −6.7 | 6.054 | 7.859 |
ADRB2 | 7 | −6.6 | 2.066 | 3.398 |
ADRB2 | 8 | −6.6 | 5.869 | 8.013 |
ADRB2 | 9 | −6.5 | 2.246 | 5.281 |
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Liu, Z.; Wang, Z.; Wang, J.; Xu, S.; Zhang, T. Uridine, a Therapeutic Nucleoside, Exacerbates Alcoholic Liver Disease via SRC Kinase Activation: A Network Toxicology and Molecular Dynamics Perspective. Int. J. Mol. Sci. 2025, 26, 5473. https://doi.org/10.3390/ijms26125473
Liu Z, Wang Z, Wang J, Xu S, Zhang T. Uridine, a Therapeutic Nucleoside, Exacerbates Alcoholic Liver Disease via SRC Kinase Activation: A Network Toxicology and Molecular Dynamics Perspective. International Journal of Molecular Sciences. 2025; 26(12):5473. https://doi.org/10.3390/ijms26125473
Chicago/Turabian StyleLiu, Zhenyu, Zhihao Wang, Jie Wang, Shiquan Xu, and Tong Zhang. 2025. "Uridine, a Therapeutic Nucleoside, Exacerbates Alcoholic Liver Disease via SRC Kinase Activation: A Network Toxicology and Molecular Dynamics Perspective" International Journal of Molecular Sciences 26, no. 12: 5473. https://doi.org/10.3390/ijms26125473
APA StyleLiu, Z., Wang, Z., Wang, J., Xu, S., & Zhang, T. (2025). Uridine, a Therapeutic Nucleoside, Exacerbates Alcoholic Liver Disease via SRC Kinase Activation: A Network Toxicology and Molecular Dynamics Perspective. International Journal of Molecular Sciences, 26(12), 5473. https://doi.org/10.3390/ijms26125473