Direct NLRP3 inflammasome inhibitors for cardiovascular therapeutics: a comparative review of synthetic and natural candidates.

The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has emerged as a critical mediator in cardiovascular diseases, connecting cholesterol crystals and metabolic danger signals to atherogenic inflammation, myocardial injury, and adverse remodeling. Using direct inhibitors that bind to NLRP3 has advantages over indirect strategies. These advantages include retaining the function of other inflammatory body sensors and the potential for oral treatment. Several synthetic compounds have progressed to clinical trials. Recently, NT-0796 demonstrated a significant reduction in C-reactive protein in obese patients with cardiovascular risk, and VTX2735 has entered Phase II trials for recurrent pericarditis. However, the clinical failure of MCC950 due to hepatotoxicity underscores persistent translational challenges in this field. Oridonin is the most rigorously validated natural product that covalently modifies NLRP3 at Cys279. However, most reported "natural NLRP3 inhibitors" did not bind biochemically. This review demonstrates a three-tier evidence classification that differentiates confirmed direct inhibitors from functional modulators. We critically explored the potential for cardiovascular applications and identified bioavailability limitations, biomarker gaps, and trial design challenges that require innovative solutions.