Decoding the Transcriptional Profile Induced by Cannabidiol in Human Cell Lines and Primary Human Cells

Background: Cannabidiol (CBD), isolated from hemp (Cannabis sativa or Cannabis indica), is receiving increasing attention for its therapeutic potential in various diseases, including viral infections. CBD has been reported to alter lateral membrane diffusion and cholesterol accessibility. However, it remains unclear which signaling pathways are affected by CBD treatment. Here, we sought to determine the effect of CBD treatment on human cell lines and primary human cells. Methods: We performed a bioinformatics analysis to identify differentially expressed genes (DEGs) in published RNA-seq datasets of CBD-treated cells, including A549, THP-1, normal human epidermal keratinocytes (NHEK), monocyte-derived dendritic cells (DC), and monocyte-derived macrophages (MDM). We then validate the A549, THP-1, and MDM sequencing data by RT-qPCR. Results: Comparative transcriptional analysis across five CBD-treated cell types identified 22 genes shared across all cell types, 138 among four, and 695 among three; these genes were enriched in endoplasmic reticulum (ER) stress, lipid metabolism, and cholesterol metabolism pathways. Transcription factor enrichment analysis identified ATF4, ATF6, XBP1, SREBF1, and SREBF2, which encode key regulators of the ER stress response and cholesterol metabolism. Conclusions: These results highlight a role for CBD in regulating the expression of transcription factors that control genes involved in ER stress, lipid, and cholesterol metabolism. Consequently, CBD treatment modulates gene expression programs in a context-dependent manner and may be associated with lipotoxic stress through dysregulation of ER stress signaling pathways.