Targeting the NLRP3 inflammasome in sepsis: Molecular mechanisms and therapeutic strategies

Sepsis is a life-threatening organ dysfunction triggered by a dysregulated host response to infection, with immune homeostasis imbalance at the core of its pathological mechanism. The NACHT, leucin-rich repeat (LRR) and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome, as an innate immune sensor, plays a critical role in the development and progression of sepsis. Upon activation, the NLRP3 inflammasome triggers caspase-1 activation, which mediates the maturation and release of IL-1β and IL-18, as well as pyroptosis. Studies have demonstrated that inhibiting NLRP3 inflammasome activation can significantly alleviate sepsis-associated systemic inflammatory responses and improve prognosis. This review systematically elucidates the pathophysiological mechanisms of sepsis, the activation mechanisms of the NLRP3 inflammasome, and its dual regulatory role in sepsis progression. Moderate NLRP3 activation aids in pathogen clearance, whereas excessive activation exacerbates cytokine storms, leading to multi-organ failure. Finally, we summarize the latest research progress on NLRP3 inhibitors currently in clinical trial stages. This article aims to provide insights for the development of NLRP3-targeted therapeutic drugs for sepsis.