Integrated whole-transcriptome analysis reveals ceRNA network dysregulation underlying methcathinone-induced synaptic
Rukui Zhou1, Chunming Xu2, Zhe Chen2
1School of Basic Medical Sciences, Shanxi University of Chinese Medicine, Jinzhong, Shanxi, China; School of Forensic Medicine, Shanxi Medical University, Jinzhong, Shanxi, China.
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Methcathinone (MCAT), a synthetic cathinone structurally analogous to amphetamine, poses substantial public health concerns due to its high addictive liability and pronounced neurotoxicity. In the present study, rat models of MCAT-induced neurotoxicity were established using low (0.5 mg/kg), medium (5 mg/kg), and high (20 mg/kg) doses. Cognitive function was assessed using the Morris water maze, while hippocampal synaptic morphology and ultrastructure were examined via Golgi staining and transmission electron microscopy. To elucidate the underlying molecular mechanisms, whole-transcriptome sequencing was performed to profile mRNAs, miRNAs, circRNAs, and lncRNAs in the hippocampus across exposure groups relative to controls. Differential expression analysis identified extensive transcriptional alterations, including 1646, 1539, and 1477 DEmRNAs; 32, 28, and 23 DEmiRNAs; 749, 728, and 753 DEcircRNAs; and 391, 369, and 371 DElncRNAs in the low-, medium-, and high-dose groups, respectively. Functional enrichment analyses consistently implicated synapse-related processes and neurodegeneration-associated pathways. Notably, activity-dependent immediate-early genes (c-Fos, Nr4a1, Arc, Egr1, Egr2, and Npas4) were uniformly downregulated across all exposure levels, indicating impaired neuronal activity-dependent transcriptional responses. Integration of multi-layered transcriptomic data enabled the construction of circRNA-miRNA-mRNA and lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks, revealing extensive post-transcriptional regulatory interactions. A core ceRNA network was identified, comprising 6 hub mRNAs, 9 miRNAs, 95 lncRNAs, and 146 circRNAs. Quantitative RT-PCR validation demonstrated high concordance with RNA-seq results, supporting the robustness of the dataset. These findings demonstrate that MCAT induces cognitive deficits and synaptic structural impairments by disrupting activity-dependent gene expression and neurotrophic signaling through complex ceRNA-mediated regulatory networks. This study provides novel mechanistic insights into MCAT-induced neurotoxicity and identifies potential molecular targets for therapeutic intervention in psychostimulant-related cognitive dysfunction.
