Recent advances in small-molecule NLRP3 inhibitors derived from natural products.

Inflammation is a crucial defensive response of the body and its dysregulation is closely associated with the pathogenesis of various chronic diseases. The NLRP3 (NOD-like receptor thermal protein domain associated protein 3) inflammasome, as a core regulatory complex in inflammation, represents a key therapeutic target for treating these conditions. Natural products, owing to their structural diversity and high binding affinity, have emerged as important sources of lead compounds for the discovery of small-molecule NLRP3 inhibitors. This review systematically summarizes the design strategies employed in modifying natural product-derived NLRP3 inhibitors, with a focused discussion on several representative derivatives, such as oridonin and tanshinones. It details the advancements achieved through structural modifications in enhancing potency, selectivity and drug-like properties. Furthermore, it evaluates several promising natural products based on their synthetic feasibility and NLRP3 inhibitory activity, thereby providing a valuable reference for the development of novel, highly effective NLRP3 inhibitors.