Circadian regulation of the S1PR1-P2X7 signalling axis in obesity-associated metabolic inflammation: molecular crosstalk and therapeutic perspectives.

Obesity is a chronic, low-grade inflammatory condition expressed by inflammation and immune damage that mediates component(s) of insulin resistance and cardiometabolic syndrome in the presence of disruption of circadian rhythms. Primary research data indicate that the interplay between biological timing and immunological signalling occurs in a synchronised manner to govern metabolic homeostasis, thereby leading us to coin the term Circadian regulation of metabolic inflammation. These signalling pathways directly affect immune cell trafficking and endothelial integrity in sphingosine-1-phosphate receptor 1 (S1PR1) or purinergic P2X7 receptor (P2X7)-mediated regulation, and inflammasome activation. This review highlights a new molecular link establishing the S1PR1-P2X7 axis between circadian rhythm and obesity-linked immunometabolic disorders. We discuss the interplay of lipid and purinergic signalling, focusing on their convergence at nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), signal transducer and activator of transcription 3 (STAT3), reactive oxygen species (ROS), and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) activation pathways that act in concert to exacerbate both fatty tissue inflammation and systemic insulin metabolic resistance. Altogether, we summarise the latest advances in receptor-based pharmacotherapy, chronotherapy, and nanomedicine-guided drug delivery aimed at restoring circadian homeostasis and metabolic balance. Understanding the circadian regulation of the S1PR1-P2X7 axis may inform new precision treatment strategies for obesity-linked metabolic diseases.