Spinal cord injury (SCI) is a debilitating condition with no effective treatment. The injury triggers a complex cascade of molecular and cellular events that drive both damage and repair processes. To explore these mechanisms, we performed a comprehensive multi-omics analysis in a rat compression model of SCI, focusing on the acute phase. Transcriptomic profiling revealed extensive gene dysregulation, highlighting early inflammation, neuronal death, and synaptic dysfunction, followed by the initiation of reparative processes. Cell type composition analysis showed a rapid infiltration of peripheral immune cells; activation of microglia; and loss of neurons, astrocytes, and oligodendrocytes. Importantly, we provide experimental support for predicted microRNA (miRNA)-mRNA-protein interactions, offering a foundation for further mechanistic studies. miRNA profiling uncovered a highly dysregulated miRNA landscape, with the miR-17∼92 cluster emerging as a key regulator of neurogenesis, synaptic activity, and cell survival. Integrative miRNA-mRNA-protein analysis identified potential therapeutic targets, including miR-20a, whose inhibition in vitro supported neurogenesis and reduced apoptosis under oxidative stress. Our findings provide new insights into the molecular mechanisms of SCI and highlight miRNAs as potential targets for therapeutic intervention.

Department of Anthropology and Human Genetics Faculty of Science Charles University 128 43 Prague Czech Republic

Department of Biochemistry and Microbiology Faculty of Food and Biochemical Technology UCT Prague 166 28 Prague Czech Republic

Department of Informatics and Chemistry Faculty of Chemistry and Technology UCT Prague 166 28 Prague Czech Republic

Department of Neuroregeneration Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Neuroscience 2nd Medical Faculty Charles University 150 06 Prague Czech Republic

GeneCore Facility Institute of Biotechnology of the Czech Academy of Sciences BIOCEV 252 50 Vestec Czech Republic

Laboratory of Gene Expression Institute of Biotechnology of the Czech Academy of Sciences BIOCEV 252 50 Vestec Czech Republic

Laboratory of Glial Biology and Omics Technologies Institute of Biotechnology of the Czech Academy of Sciences BIOCEV 252 50 Vestec Czech Republic

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