The human innate immune system plays a crucial role as the first line of defense against the invasion of harmful substances, thereby ensuring the maintenance of bodily homeostasis and normal tissue function. Innate immunity is triggered by pattern recognition receptors (PRRs) which, in precise coordination with the acquired immune response and cytokine regulation, enable the identification and elimination of harmful substances. PRRs can recognize either pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) [1]. PAMPs encompass conserved fragments commonly found in microorganisms, such as lipopolysaccharide (LPS) form the cell wall of Gram-negative bacteria, bacterial flagellin, nucleic acids from bacteria or viruses, and microbial secretion systems. DAMPs, on the other hand, are endogenous molecules released due to cellular stress or damage, including uric acid crystals, ATP, high mobility group box 1 (HMGB1), the heat-shock proteins, and more [2], [3], [4].

NOD-like receptors (NLRs) belong to the family of PRRs, and their various family members play an indispensable role in the human immune system. Among the NLRs, the NLRP3 inflammasome has been extensively studied. Research since 2004 has identified it as a pivotal mediator of inflammation associated with aseptic pro-inflammatory signals in a wide range of acute and chronic human diseases [5]. These include conditions such as cryopyrin-associated periodic syndromes (CAPS), metabolic diseases like gout, type 2 diabetes mellitus (T2DM), nonalcoholic steatohepatitis (NASH), atherosclerosis (AS) and central nervous system diseases such as Alzheimer 's disease (AD) and Parkinson 's disease (PD) [6], [7], [8], [9], [10], [11], [12]. In addition, NLRP3 has also been linked to cancer and depression [13], [14], [15], [16].

The activation pathway of NLRP3 inflammasome mainly includes two stages: priming and activation. During the priming phase, PRRs up-regulate the expression of protein precursors through the NF-κB pathway upon recognizing DAMPs and PAMPs. These protein precursors undergo post-translational modifications to form NLRP3 double-ring cage oligomers. Subsequently, ATP exchange occurs, leading to the opening of inactive double-ring cage oligomers, and the recruitment of the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) domain, culminating in assembly and final activation [4]. The activation pathway of inflammasome presents a promising avenue for therapeutic interventions in these diseases. The development of inflammasome inhibitors has long been the focus of researchers. Currently, biologics that mainly target the NLRP3 effector molecule IL-1β have been marketed for the treatment of diseases caused by NLRP3 overactivation. In contrast, most small molecule inhibitors directly targeting NLRP3 are still under exploration and optimization and have not yet entered clinical use.

NLRP3 inflammasome is a multiprotein complex that assembles and activates through a series of intricate protein-protein interactions (PPIs). These PPIs serve as the foundation for essential cellular processes [17]. For a long time, due to the unique characteristics of their contact interface, PPIs were deemed undruggable targets. However, following the approval of Venetoclax for the treatment of acute myeloid leukemia in 2016 [18], there has been a gradual increase in PPI inhibitors, offering fresh perspectives to researchers. Surprisingly, the potential of targeting PPIs has not yet been fully explored the development of NLRP3 inhibitors. In this review, we concentrate on the PPIs within the NLRP3 inflammasome activation pathway, and provide an overview of inhibitors that can interfere with these critical protein-protein interactions. Our goal is to shed new light on the discovery of inhibitors targeting the NLRP3 inflammasome, offering innovative directions for future research in this field. Fig. 1.