Bulk Transcriptomic Profiling of Human Carotid Plaques Identifies Macrophage-Enriched Signatures and NCOR2 Upregulation in Symptomatic Disease

Background/Objectives: Symptomatic carotid plaques exhibit inflammatory and structural-cell-associated expression signatures. We compared bulk plaque transcriptomes by clinical presentation and explored the transcriptional context of nuclear receptor corepressor 2 (NCOR2). Methods: Carotid endarterectomy specimens from 19 symptomatic and 13 asymptomatic patients underwent ribosomal RNA-depleted bulk RNA sequencing. Differential-expression and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were complemented by exploratory NCOR2-centred signed co-expression and transcription-factor target-set enrichment using ChEA 2022 and TRRUST 2019. Cell-type deconvolution was not performed. Results: Symptomatic plaques showed higher CD68, CD163, and NCOR2 expression and lower CNN1 and KDR expression. Immune and endolysosomal annotations were prominent. The NCOR2-associated visualisation highlighted lipid-handling, lysosomal, antigen-presentation, and matrix-remodelling genes, including APOE, TREM2, CTSD, CTSB, CIITA, and MMP9. Regulatory target-set enrichment included LXR/NR1H3, SMRT/NCOR2, TFEB, and SPI1-related signatures. These tissue-level associations do not establish functional pathway activity or direct regulation by NCOR2. Conclusions: Symptomatic carotid disease was associated with a macrophage-enriched bulk expression signature and an NCOR2-associated lipid and lysosomal context. The findings support testable hypotheses involving cellular composition, compensatory responses to stress, and maintenance of adapted cell states. Independent replication, cell-specific localisation, and functional studies are required before biomarker or therapeutic relevance can be established.