Therapeutic Targeting of NLRP3 Inflammasome and JNK Pathways in Inflammation-Induced Insulin Resistance

Inflammation is a physiological response of the organism to noxious stimuli, physical, chemical, or biological, with a chronic, low-grade inflammatory state, which suggests that inflammation may be an underlying mechanism by which obesity leads to insulin resistance. Among the array of molecular mechanisms implicated in this pathophysiological state, the NLRP3 inflammasome and the c-Jun N-terminal kinase (JNK) pathway have emerged as central mediators of immune–metabolic crosstalk. NLRP3 inflammasome and the c-Jun N-terminal kinase (JNK) signaling pathway are principal regulators of immunometabolism, the interface between immune cells and metabolism. The NLRP3 inflammasome, a protein complex, detects danger signals and induces the activation of caspase-1, leading to the secretion of inflammatory cytokines and pyroptosis. The JNK, a stress-activated kinase, participates in inflammation and metabolic derangements, such as insulin resistance. This review provides an extensive overview of the molecular mechanisms through which such pathways cause insulin resistance and summarizes recent pharmacologic strategies to control their activity. Highlighted are recent developments in addressing these inflammatory nodes, an assessment of preclinical and clinical data, and a discussion of the difficulties and potential paths for turning these discoveries into treatments.