How gene regulation may shape CB1R activity in disease

The endocannabinoid system (ECS) is a highly plastic signaling network whose components are dynamically regulated in a context-dependent manner. Among its components, the cannabinoid type 1 receptor (CB1R), encoded by the CNR1 gene, is involved in multiple processes, including neuromodulation, neurodevelopment, metabolic regulation, nociception, appetite regulation, redox homeostasis, and inflammatory signaling. Alterations in CB1R expression occur selectively and progressively and have been linked to numerous metabolic disorders, cancer, and neurodegenerative diseases. Recent studies have begun to unveil the transcriptional and epigenetic mechanisms regulating CB1R expression, involving inflammatory transcription factors, nuclear receptors, metabolic regulators, redox-sensitive pathways, hormone-responsive factors, as well as chromatin remodeling marks and promoter methylation. These modulatory programs collectively shape CB1R abundance and availability and may critically influence the efficacy and safety of cannabinoid-based therapies. In this review, we discuss current knowledge of the transcriptional and epigenetic regulation of the CNR1 gene in response to various pathologies and drugs, highlighting context-dependent modulatory mechanisms. Additionally, we performed an in silico analysis to identify potential transcription factor binding sites (TFBS) in the CNR1 promoter and to elucidate candidate regulatory networks underlying its differential expression in health and disease.