Mechanistic insights into natural product-driven modulation of NLRP3-inflammasome signalling in metabolic syndrome.

Abstract

Introduction: Metabolic syndrome (MetS) comprises a cluster of interrelated metabolic abnormalities, including obesity, insulin resistance, dyslipidaemia and hypertension, mainly driven by chronic low-grade inflammation. Among innate immune pathways, the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has emerged as a critical molecular link between metabolic stress and inflammatory signalling, promoting caspase-1 activation, interleukin (IL)-1β/IL-18 maturation and pyroptosis across metabolically active organs such as adipose tissue, liver and pancreas. Persistent NLRP3 activation, triggered by mitochondrial dysfunction, oxidative stress, ionic imbalance and impaired autophagy, contributes directly to insulin resistance, hepatic steatosis, β-cell dysfunction and cardiometabolic complications, highlighting natural products as promising multi-target modulators capable of attenuating NLRP3-driven metabolic inflammation.

Methods: The literature search was conducted in PubMed and Scopus to identify recent studies investigating phytochemical-mediated modulation of NLRP3 inflammasome signalling in MetS from 2020 to December 2025. Eligible studies were screened for mechanistic relevance, with particular emphasis on NLRP3-centred pathways.

Results and conclusion: The consolidated evidence demonstrates that diverse classes of natural products, including flavonoids, phenolic acids, terpenoids and other bioactive compounds, effectively attenuate NLRP3 activation by suppressing NF-κB-dependent priming, limiting mitochondrial ROS generation, stabilising lysosomal integrity, enhancing AMPK-SIRT signalling and promoting autophagy. Several plant extracts and complex formulations exhibit coordinated metabolic and anti-inflammatory benefits across adipose, hepatic, vascular, neural and renal models of MetS. In addition to summarising their regulatory effects on key inflammatory and metabolic pathways, the review also addresses available toxicity and safety data, thereby providing a more comprehensive perspective on their therapeutic relevance. Overall, this review presents an integrated synthesis of mechanistic and preclinical evidence highlighting natural products as multi-target modulators of NLRP3-mediated metabolic inflammation.