Platycodon grandiflorus Polysaccharide Attenuates Inflammation by Inhibiting NLRP3 Inflammasome Activation via the...

Dysregulated activation of the NLRP3 inflammasome is a key driver in the pathogenesis of numerous inflammatory disorders. This study aimed to evaluate the protective effect of Platycodon grandiflorus polysaccharide (PGPS_t) against NLRP3-inflammasome-mediated inflammation and elucidate its underlying mechanisms. An in vitro inflammatory model was established in porcine alveolar macrophages (3D4/21) using LPS/ATP co-stimulation. The effects of PGPS_t were assessed by measuring inflammasome activation, intracellular reactive oxygen species (ROS) generation, and pro-inflammatory cytokine secretion. Molecular docking, alongside inhibitors (NAC, MCC950) and siRNA targeting NEK7, was employed to probe the involved mechanisms. PGPS_t significantly suppressed NLRP3 inflammasome assembly and activation, reduced caspase-1 cleavage, and decreased the maturation and release of IL-1β and IL-18. It exerted its inhibitory effects through dual mechanisms: scavenging intracellular ROS and directly binding to NEK7 and NLRP3 to disrupt their interaction, as supported by molecular docking. The anti-inflammatory effect was diminished upon NEK7 knockdown. In conclusion, PGPS_t is an effective natural inhibitor of the NLRP3 inflammasome, functioning through ROS clearance and direct interference with the NLRP3-NEK7 interaction. These findings propose PGPS_t as a promising therapeutic candidate and further validate NEK7 as a potential target for treating NLRP3-driven inflammatory diseases.