The NLRP3 inflammasome as a bridge between myocardial infarction and depression: mechanisms, bidirectional link, and therapeutic potential.

Myocardial infarction (MI) and depression frequently co-occur and form a bidirectional relationship that worsens patient outcomes, with inflammation serving as a core mechanism linking these two disorders. The NLRP3 inflammasome, a key component of the innate immune system, plays a pivotal role in sterile inflammatory responses. This review systematically summarizes the structural characteristics, activation mechanisms, and pathophysiological functions of the NLRP3 inflammasome, with a particular focus on its involvement in the pathogenesis of MI and depression and the bidirectional relationship between the two diseases. We comprehensively elaborate on the role of the NLRP3 inflammasome as a molecular bridge between MI and depression, exploring mechanisms including oxidative stress and mitochondrial dysfunction, ATP-P2X7 signaling and calcium pathways, peripheral and central inflammation, sympathetic and vagus nerve pathways, the gut microbiota-gut-brain axis, neurotransmitter and neurotrophic metabolic dysregulation, VEGF-mediated vascular permeability, metabolic disturbances, and neuroendocrine dysfunction. We also discuss the clinical implications of NLRP3-related molecules as biomarkers for predicting treatment responses and analyze the role of the NLRP3 inflammasome in treatment sensitivity and resistance within heart-brain comorbidity. Finally, we summarize current therapeutic strategies targeting the NLRP3 inflammasome and propose future research directions. We propose that NLRP3 inflammasome activation is a common upstream driver of both cardiac remodeling and depressive neuroinflammation, and that its persistence explains why standard therapies often fail in comorbid patients. Targeting NLRP3 may therefore break the self-sustaining inflammatory loop that perpetuates the comorbidity. Targeting the NLRP3 inflammasome may represent a novel strategy for breaking the vicious cycle between MI and depression, offering potential benefits for both cardiovascular and mental health. Importantly, direct evidence for NLRP3 as a causal mediator in comorbidity-specific systems remains limited; we therefore present this as an integrative framework that synthesizes parallel pathways and identifies critical knowledge gaps.