Integrating Bulk and Single-Cell Transcriptomics to Identify the Role of CPT1C and Its Associated Genes in Major Depressive Disorder and Predict Targeted Therapeutics

<title>Abstract</title> <p>Background Major depressive disorder (MDD) has a complex pathogenesis, and the role of carnitine palmitoyltransferase 1C (CPT1C)-associated molecular networks remains unclear. Methods Bulk RNA-seq datasets (GSE201332 and GSE52790) and single-cell RNA-seq data (GSE144136) were integrated to identify CPT1C-associated genes in MDD. Differential expression, protein-protein interaction analysis, machine learning, receiver operating characteristic analysis, gene set enrichment analysis, drug screening, molecular docking, molecular dynamics simulations, cell-cell communication, pseudotime, metabolic profiling, and virtual CPT1C knockout analyses were performed. Results Eighty CPT1C-associated candidate genes were identified, and ATF1 and PLEKHA3 were validated as consistently downregulated key genes with diagnostic value. These genes were associated with inflammatory, synaptic, and metabolic pathways. Single-cell analysis indicated that inhibitory neurons were the major cellular context of the CPT1C/ATF1/PLEKHA3 axis. MDD samples showed altered NRG3-ERBB4 signaling, inhibitory neuron subtype-specific metabolic heterogeneity, and disease-specific communication rewiring. Virtual CPT1C knockout suggested mitochondrial electron transport disruption. Pentosan polysulfate was predicted as a potential compound targeting ATF1 and PLEKHA3, with stable binding supported by docking and simulations. Conclusions This study suggests that CPT1C-associated ATF1 and PLEKHA3 may contribute to MDD through metabolic-synaptic dysfunction in inhibitory neurons and identifies pentosan polysulfate as a candidate therapeutic compound requiring further validation.</p>