Targeting P2X7 receptor/NLRP1 inflammasome axis and gut dysbiosis: A mechanistic review of pyroptosis in metabolic inflammation

Background Obesity and type 2 diabetes (T2D) are chronic metabolic disorders characterized by persistent low-grade systemic inflammation. While the NLRP3 inflammasome is well-documented, the NLRP1 inflammasome has recently emerged as a proximal molecular "“tripwre” that initiates pyroptotic cell death and cytokine maturation, driving metabolic decline.MechanismsHyperglycemia and lipotoxicity induce cellular stress, leading to the release of extracellular ATP (eATP) through Pannexin-1 channels. Simultaneously, dysbiosis-induced “leaky gut” facilitates the systemic translocation of lipopolysaccharides (LPS). These DAMPs and PAMPs activate the P2X7 receptor (P2X7R) and Toll-like receptor (TLR) signaling pathways, respectively, triggering the NLRP1 inflammasome. Once activated via functional degradation, the human NLRP1 C-terminal fragment recruits caspase-1, either directly via its CARD domain or through the ASC adaptor, to cleave gasdermin D (GSDMD) and pro-inflammatory cytokines (IL-1β and IL-18). This process executes inflammatory pyroptosis in adipocytes and pancreatic β-cells. Crucially, NLRP1 also serves as an intrinsic negative regulator of the Th17/STAT3 axis; its dysregulation leads to uncontrolled IL-17 production and the activation of JNK/NF-κB pathways. This signaling cascade inhibits the IRS-1/PI3K/AKT axis and impairs insulin secretion by downregulating GLUT2, PDX-1, and GCK.Consequences and treatmentsChronic NLRP1 hyperactivation fosters a self-perpetuating “vicious cycle” of tissue damage, insulin resistance, and β-cell attrition, leading to macrovascular and microvascular complications. To disrupt this cascade, a multi-faceted therapeutic approach is required. Restoring the intestinal barrier through probiotics and short-chain fatty acids (SCFAs) can limit the circulation of inflammatory primers. Concurrently, targeting the P2X7R/NLRP1 axis with specific antagonists and inflammasome inhibitors provides a pragmatic strategy to reduce systemic inflammation. This review elucidates the complex interplay between these pathways and proposes a combination therapy to mitigate the chronic inflammatory burden of obesity and T2D.