<p>Purinergic signaling plays an important role in hematopoietic stem/progenitor cell (HSPCs) trafficking, and the role of extracellular alarmin adenosine triphosphate (ATP), a major purinergic signaling mediator, is well established. Another alarmin, uridine diphosphate glucose (UDP-glucose), has also been reported to promote HSPCs trafficking after binding to the P2Y14 purinergic receptor. The molecular basis for this phenomenon, however, remains unclear, especially because UDP-glucose alone does not chemoattract HSPCs. To address this question, we hypothesize that UDP-glucose's role in stem cell trafficking may involve promoting the formation of membrane lipid rafts (MLRs) and enhancing intracellular activation of the Nlrp3 inflammasome, which we have previously identified as essential regulators of HSPCs migration. We found that UDP-glucose promotes HSPCs mobilization not only in response to the pro-mobilizing agent G-CSF but also in response to AMD3100. Furthermore, for the first time, we demonstrate that UDP-glucose also promotes homing and engraftment of HSPCs. We also evaluated the biological effects of a newly synthesized UDP-glucose analog, MRS2690. Our studies included HSPCs in vitro and in vivo trafficking assays, immunostaining and confocal analysis to assess MLRs formation on HSPCs, supported by metabolic analyses to identify metabolites involved in MLRs formation.&#xa0;Our data support our hypothesis that activation of the P2Y14 receptor on HSPCs by its ligands positively modulates cell trafficking, primarily by promoting lipid raft formation and Nlrp3 inflammasome activation. Interestingly, one of the components of MLRs upregulated in response to UDP-glucose is sphinganine, which serves as a fundamental building block and intermediate in the de novo biosynthesis of sphingolipids.</p> Graphical Abstract <p></p>