A Natural Metabolite and Inhibitor of the NLRP3 Inflammasome: 4-Hydroxynonenal

The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, crucial in the innate immune response, is linked to various human diseases. However, the effect of endogenous metabolites, like 4-hydroxynonenal (HNE), on NLRP3 inflammasome activity remains underexplored. Recent research highlights HNE's inhibitory role in NLRP3 inflammasome activation, shedding light on its potential as an endogenous regulator of inflammatory responses. Studies demonstrate that HNE blocks NLRP3 inflammasome-mediated pyroptosis and IL-1β secretion. Additionally, covalent targeting emerges as a common mechanism for inhibiting NLRP3 inflammasome assembly, offering promising avenues for therapeutic intervention. Further investigation is needed to understand the impact of endogenous HNE on NLRP3 inflammasome activation, especially in settings where lipid peroxidation byproducts like HNE are produced. Understanding the intricate interplay between HNE and the NLRP3 inflammasome holds significant potential for unraveling novel therapeutic strategies for inflammatory disorders.