Characterized by its capacity to induce organ failure, sepsis constitutes a life-threatening pathological state with high incidence and mortality rates. Current treatments primarily focus on antimicrobial therapy and organ support, lacking direct interventions targeting the restoration of cellular or organelle function. Among these mechanisms, mitochondrial dysfunction and overactivation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome stand out as key pathological hallmarks. As a classic inflammasome, the NLRP3 inflammasome, upon activation, drives cellular pyroptosis and massive release of inflammatory mediators. Beyond their role as cellular energy generators, mitochondria participate in the modulation of inflammatory responses and oxidative stress control. Mitochondrial quality control (MQC) serves as a prerequisite for the orderly performance of mitochondrial physiological functions. Disruption of MQC invariably results in mitochondrial dysfunction, triggering liberation of mitochondrial reactive oxygen species (mtROS) along with mitochondrial damage-associated molecular patterns (mtDAMPs), which serve as direct triggers for NLRP3 inflammasome formation and stimulation. This process disrupts MQC, exacerbates mitochondrial dysfunction, and forms a mutually reinforcing "MQC imbalance-NLRP3 overactivation" vicious cycle that drives disease progression. This review aims to: (1) systematically elucidate the complex bidirectional regulatory mechanisms between the NLRP3 inflammasome and MQC in the context of sepsis, (2) summarize the latest research progress on targeted intervention strategies based on this vicious cycle, and (3) discuss the challenges in clinical translation and future directions of these strategies.
Liao et al. (Thu,) studied this question.