Osteoarthritis (OA) is a clinically common degenerative joint disorder characterized by synovial hyperplasia, progressive destruction of articular cartilage and secondary osteophytes, with the knee being the main peripheral joint involved (28). The common symptoms of OA are pain and joint stiffness, with a small number of patients eventually experiencing loss of joint function. On a macroscopic level, the causes of OA include a variety of factors such as ageing, obesity, trauma, and excessive joint loading. On a microscopic level, the pathological cause of OA is the imbalance of cellular metabolism in the joint leading to the overexpression of inflammatory factors and alterations in the cartilage matrix microenvironment (29–31). The majority of OA therapeutic treatments currently available are palliative, concentrating on pain management and anti-inflammation. At present, knee arthroplasty is the ultimate treatment option for OA, but it has site restrictions, serious side effects, and is irreversible (32). Understanding the pathological process of OA and further researching effective treatments are vital in order to limit the generation of inflammatory mediators and cartilage breakdown in the joints.

The molecular mechanisms of NLRP3-mediated pyroptosis have received widespread attention during the progression of OA (32), which can lead to the deterioration of cartilage within the joint and inflammation of the synovium. Research indicates higher levels of NLRP3 protein manifestation in synovial specimens obtained from individuals suffering from knee osteoarthritis. The NLRP3 inflammasome speeds up the maturation of IL-1β and IL-18, which have a crucial role in the pathogenesis and progression of OA. Xin et al. (33) confirmed that NLRP3-mediated pyroptosis is closely associated with synovitis in temporomandibular joint osteoarthritis (TMJOA). Additionally, the utilization of the Caspase-1 inhibitor Ac-YVAD-cmk and the NLRP3 inhibitor MCC950 can disrupt the activation of NLRP3 and hinder pyroptosis in synovial cells, ultimately leading to a decrease in local synovitis. Hence, the NLRP3/Caspase-1 signaling pathway plays a crucial role in the initiation and advancement of osteoarthritis, making the pyroptosis process highly significant in this context.

NF-κB is a crucial upstream activator of the NLRP3 inflammasome, which by increasing the expression of NLRP3 related components causes the inflammasome to prime and assemble. Consequently, it may trigger the oversecretion of inflammatory cytokines, accelerating cartilage loss and fibrosis in the knee joint. The purinoceptor P2X7R, which serves as a significant trigger for inflammation, has gained considerable interest as a possible target for treating OA. Li et al. (34) discovered that activated P2X7 receptor enhances extracellular matrix breakdown and induces inflammatory cell pyroptosis in OA chondrocytes via the interaction between NF-κB and NLRP3, thereby worsening symptoms of osteoarthritis. Yan et al. (35) found that Licochalcone A (Lico A) has the ability to hinder the activation of NLRP3 inflammasome and chondrocytes pyroptosis induced by LPS through the Nrf2/HO-1/NF-κB axis, thereby reducing the advancement of osteoarthritis in destabilization of the medial meniscus (DMM)-induced OA mouse model. Additionally, Jin et al. (36) compared the effects of diets rich in different types of dietary fatty acid (FA) on obesity-associated OA and found that diets rich in n-3 PUFAs had anti-inflammatory and anti-pyroptotic properties, the mechanism of which may be closely related to the NF-κB/NLRP3 crosstalk in chondrocytes. Collectively, inhibition of NF-kB signaling to modulate NLRP3-mediated pyroptosis is a potential strategy for OA treatment which could inhibit chondrocyte pyroptosis and increase collagen II expression, thereby attenuating OA progression.

Elevated levels of ROS are widely believed to play an essential role in the functional degeneration of articular cartilage during the progression of OA. Hypoxia of synovial tissue is one of the key pathological features of synovitis, and the hypoxic state of the microenvironment within the knee cavity can exacerbate synovial inflammation in a number of ways (31). A series of reactions caused by hypoxia are involved in the pathological processes related to osteoarthritis, including synovial inflammation, cartilage destruction and angiogenesis. Liu et al. (37) demonstrated that ubiquitin specific protease 7(UPS7) promotes OA progression through the NOX4/ROS/NLRP3 axis. The inhibition of NOX4 ubiquitination by UPS7 prevents its degradation, resulting in elevated production of ROS. These ROS can then activate the NLRP3 inflammasome, leading to enhanced secretion of IL-1β and IL-18, as well as the pyroptosis of chondrocytes. The activation of the specific adenosine A3 receptor (A3AR) has demonstrated strong anti-inflammatory effects in numerous diseases. Bai et al. (31) found that activation of A3AR could reduce the severity of anterior cruciate ligament transection (ACLT) model by inhibiting NLRP3-mediated pyroptosis and downstream inflammatory cascades. In particular, the activation of A3AR inhibits the progression of OA and alleviates the perception of pain by blocking the signaling pathway of ROS/NLRP3/GSDMD. Hence, reducing the amount of ROS to weaken the activation of the NLRP3 inflammasome could be a promising approach to intervene in OA and should be explored further ( Figure 2 ).

Osteoarthritis involves the degeneration of cartilage, fibrosis of the synovial tissue, and the presence of chronic inflammation. Chondrocytes and fibroblast like synoviocytes (FLSs) play a significant role in the molecular process of NLRP3-mediated pyroptosis in osteoarthritis. The NF-κB signaling and NLRP3 interaction can result in chondrocyte pyroptosis, which in turn enhances the release of inflammatory cytokines and ultimately leads to cartilage degeneration.Additionally, ROS levels play a key role in the degeneration of articular cartilage function. Excessive ROS can activate the NLRP3 inflammasome and its downstream pathways, further exacerbating cartilage loss. The development of synovial fibrosis is primarily caused by the pyroptosis of FLSs, with the NLRP3 inflammasome playing a role in the classical pyroptotic pathway, which worsens the progression of synovial fibrosis. The disparity in cellular metabolism levels within the knee joint causes an overabundance of inflammatory substances and changes in the microenvironment of the cartilage matrix, ultimately leading to the onset of OA.

Rheumatoid arthritis (RA) is a chronic inflammatory bone disease, an autoimmune degenerative disease characterized by joint synovitis, which is characterized by polyarticular and symmetrical damage to the facet joints of the hands and feet, and can eventually lead to joint pain and deformity (38). The NLRP3 inflammasome is closely related to RA, and its abnormal activation is important in guiding the inflammatory response and the development of immune diseases. The NLRP3-mediated pyroptosis could secrete large amounts of inflammatory factors, which penetrate into synovial tissue and lead to synovial hyperplasia, thereby exacerbating the histopathological changes of RA. Wu et al. (39) successfully constructed an adjuvant arthritis (AA) rat model and investigated the role of acid-sensitive ion channels (ASICs) in chondrocyte pyroptosis. The discovery was made that the buildup of inflammatory substances in joints causes a reduction in the acidity of synovial fluid and triggers ASIC1a, which facilitates the entry of calcium ions into cells. Simultaneously, the increase in intercellular calcium promotes the production, clustering, and formation of the NLRP3 inflammasome, subsequently leading to the activation of caspase-1. In addition to showcasing the significance of synovial fluid pH in the development of RA, this study uncovers the role of NLRP3-mediated pyroptosis in the progression of RA.

The activation of the NLRP3 inflammasome is widely recognized as a process that occurs in two steps. As mentioned above, the NF-κB pathway is involved in the initiation of NLRP3 and IL-1β gene transcription in the priming step; and the NLRP3 inflammasome can be activated by PAMPs or DAMPs in the activation step. Various molecules or cellular events, such as malfunctioning mitochondria and mitochondrial DNA, ROS, ion flow, and lysosomal harm, can trigger the activation of NLRP3 (40). Among them, Ge et al. (41) found that punicalagin (PUN), an active substance extracted from pomegranate peel, has the ability to hinder the activation of the NF-κB signaling pathway, consequently restraining the occurrence of pyroptosis in macrophages. Partially alleviating the progression of RA can be achieved by inhibiting the pro-inflammatory impact of macrophages via the NF-κB signaling pathway, offering a fresh perspective for treatment. Hong et al. (42) confirmed that the presence of low oxygen levels in the surrounding area of the joint worsens the development of inflammation within the joint in individuals with rheumatoid arthritis. They discovered that heightened levels of HIF-1α in FLSs could worsen synovitis through FLSs pyroptosis, whereas the rise in GRK2 expression resulting from oxidative stress can contribute to the elevation of HIF-1α expression. Overall, their study showed that hypoxia induced FLSs pyroptosis by activating the ROS/GRK2/HIF-1α/NLRP3 pathway, whereas monomeric derivatives of paeoniflorin (MDP) reduced hypoxia-induced pyroptosis in FLSs by inhibiting the GRK2/HIF-1α axis.

The primary mediator of cartilage destruction in rheumatic illnesses is the inflammatory cytokine IL-1, which is mainly derived from macrophages. Walle et al. (43) discovered that the absence of the RA-susceptibility gene A20 in macrophages greatly increased NLRP3-mediated caspase-1 activation, pyroptosis and IL-1β secretion. The findings demonstrate that A20 functions as a new inhibitor of NLRP3 inflammasome activation. MicroRNAs (miRNAs) can regulate cellular processes (cell proliferation, apoptosis, etc.) and are widely involved in inflammatory and pyroptotic responses. Jiang et al. (44) revealed that miR-144-3p could regulate NLRP3-mediated chondrocyte pyroptosis by inhibiting the expression of the target gene PTEN and suppressing the activation of PINK1/Parkin signaling. Further research into the pathogenesis of RA could help develop effective targeted drugs and inhibitors, offering new therapeutic options for the relief of RA symptoms ( Figure 3 ).

Multiple immune cells are involved in the development of RA. The basic pathological features of RA include persistent synovial inflammation and articular cartilage degeneration. A decrease in the PH of synovial fluid is one of the physiological manifestations of RA, and extracellular acidosis induces chondrocyte ASIC1a activation, leading to the influx of Ca2+ into cells and activation of NLRP3 inflamasome. The mechanism may be related to the activation of the calpain-2/calcineurin pathway. Macrophage pyroptosis can result in an overactive immune response and the release of inflammatory mediators, which can contribute to the breakdown of bone and cartilage. The NF-κB pathway plays an important interactive role in NLRP3-mediated pyroptosis of macrophage. In FLSs, the classical pyroptotic pathway is mainly activated by ROS and LPS. Overall, multiple cellular pyroptotic pathways mediated by the NLRP3 inflammasome collectively exacerbate the histopathological changes in RA.

Gouty arthritis (GA) is a metabolic disorder resulting from an abnormality in the metabolism of purine. It is characterised by deposits of MSU crystals in the articular cartilage, synovial sac and other tissues stimulating the production of inflammation, which leads to joint pain and swelling (45). MSU deposition can induce the inflammasome and activate the secretion of the inflammatory cytokines IL-1β and IL-18. Meanwhile, studies have reported increased levels of NLRP3, IL-1β and IL-18 in the serum and joint fluid of gout patients compared to healthy controls (46, 47). The NLRP3-mediated pyroptosis may be involved in the crosstalk between MSU-activated gout and the inflammatory cascade. Tian et al. (46) constructed a MSU-induced GA mouse model and found that inhibition of the NLRP3-mediated pyroptosis using inhibitors improved joint inflammation in the mouse model. Targeting the NLRP3 inflammasome could be an efficient approach for managing and preventing GA, as it plays a crucial role in the development and advancement of inflammation and chronic ailments.

Luo et al. (40) found that corilagin has the ability to restrict the generation of mitochondrial ROS, thereby inhibiting the association between TXNIP and NLRP3. In combination, corilagin inhibits the ROS/TXNIP/NLRP3 pathway to suppress inflammasome activation and pyroptosis, indicating its potential as an antioxidant in reducing GA dependent on NLRP3. And Hao et al. (48) proved the important value of the NF-κB pathway in GA development. They used JQ-1, a BRD4-specific inhibitor, to inhibit MSU-induced macrophage pyroptosis and reduce levels of NLRP3 inflammasome. The results indicate that the expression of Brd4 in the joint was associated with the damage to the joint and the occurrence of pyroptosis cascade events in GA through the signaling pathway of NF-κB/NLRP3/GSDMD. Moreover, the P2Y14R, which is a G-protein-coupled receptor, has the ability to suppress the production of cyclic adenosine monophosphate (cAMP) in immune cells, making it a promising candidate for controlling inflammatory reactions. Li et al. (49) found that P2Y14R knockout disrupted MSU-induced histopathologic changes in rat synovium and simultaneously inhibited NLRP3 inflammasome activation in synovial tissues, which was reversed by reducing cAMP levels. The results of their study revealed the involvement of the P2Y14R/cAMP/NLRP3 signaling pathway in acute gouty arthritis, indicating that intracellular cAMP has a distinct function in facilitating communication between P2Y14R activation and the inflammatory process during GA flares.

Overall, the pathogenesis of GA is relatively complex. The presence of MSU crystals stimulates the generation of diverse inflammatory substances and chemokines, thereby facilitating the infiltration of neutrophils and monocytes (50). The occurrence of GA is significantly influenced by pyroptosis mediated by the NLRP3 inflammasome, and numerous investigations have shed light on the activation or control mechanism of the NLRP3 inflammasome in the progression of GA. However, the exact role and mechanism of NLRP3 inflammasome in GA is still not fully elucidated, and more studies would be necessary to clarity its mechanism with GA in future ( Figure 4 ). And the regulatory element of NLRP3-mediated pyroptosis in arthritis are listed in Table 1 .

GA is characterized by MSU deposition stimulating the onset of joint inflammation. The NLRP3 inflammasome is induced by aggregation of MSU during pathogenesis, which then induces the activation of caspase-1 and IL-1β. Multiple pathways including mitochondrial dysfunction, ROS and NF-κB are involved in NLRP3-mediated macrophage pyroptosis in the development of GA. NLRP3 inflammasome activation may be a new target for the treatment of GA.

The NLRP3 inflammasome is closely associated with various arthritic conditions, and its abnormal activation is of great significance for the inflammatory responses as well as the development of immune diseases, and is a therapeutic target for the alleviation of inflammatory bone diseases (8). Among the drug treatment strategies for arthritis, drugs that directly block and indirectly affect the NLRP3-mediated pyroptosis pathway can be classified according to their different activation types. First, NLRP3 inflammasome direct inhibitors include: 1) NLRP3 direct inhibitors, such as icariin (ICA), CY-09, MCC950, and leojaponin; 2) caspase direct inhibitors, such as Ac-YVAD-cmk and NSC697923.

Various molecular mechanisms have been implicated in the NLRP3 activation pathway, including potassium efflux, calcium signaling, lysosomal damage, and mitochondrial dysfunction (17). Thus, depending on their mechanism of action, indirect inhibitors of the NLRP3-mediated pyroptosis pathway can be classified as:1) NF-κB inhibitors, such as punicalagin, morroniside, loganin, dietary fatty acid, Lico A and baicalein E (BF-2); 2) ROS or mitochondrial function inhibitors, such as monomeric derivatives of paeoniflorin (MDP), A3AR agonist (CF101), gallic acid, corilagin, resveratrol (Res); 3) ASIC1a inhibitors, such as amiloride and Pslogotoxin-1 (PcTx1); 4) P2Y14 receptor antagonists, such as HQL6 and 3-amide-5-aryl benzoic acids; 5) GSDMD inhibitors, such as necrosulfonamide (NSA); 6) PKA activators, such as wedelolactone; 7) AMPK activators, such as SDF-1. In addition, a number of studies have reported that Chinese herbal ingredients can interfere with the NLRP3 inflammasome in the treatment of RA, including Huai Qi Huang Granules (HQH), Baihu-Guizhi decoction(BHGZD), Jinwujiangu Capsule (JWJG capsule). Traditional Chinese medicine ingredients can affect the NLRP3 inflammasome to activate and reverse the imbalance of the inflammatory immune system during the onset and progression of RA, but its specific mechanism is still unclear.

miRNAs are noncoding small RNA molecules composed of 18-23 nucleotides that can negatively regulate gene expression (71) and are widely involved in inflammation and pyroptosis pathway. And a number of studies have reported that miRNAs play an important role in the NLRP3-mediated pyroptosis pathway. Different miRNAs are known to play regulatory roles in the progression of OA (miR-107, miR-155, miR-140-5p, miR-326, miR-219a-5p), RA (MiR-144-3p, MiR-135b-5p) and GA (miR-223-3p). Therefore, we summarize recent studies related to miRNAs/NLRP3 signaling with function of regulating the development of arthritis ( Table 3 ).

Various types of arthritis exhibit increased joint inflammation and release of inflammatory cytokines, and understanding the mechanisms of pro-inflammatory cytokine expression and exploring potential therapeutic approaches offers new strategies for the management of these diseases. Complement activation contributes to inflammation, which aids in the pathogenic processes of autoimmune disorders. PTX3 regulates complement function by interacting with C1q and factor H, playing a crucial role in the innate immune system (61). Wu et al. (61) highlight the role of complement C1q and its ligand PTX3 in enhancing the synthesis of inflammatory cytokines, specifically IL-6. This leads to the over-activation of NLRP3 and pyroptosis induced by PTX3 and C1q, creating a positive feedback loop. Their findings suggest a new potential treatment strategy targeting pyroptosis-mediated persistent inflammatory cytokine release.

GSDMD-targeting treatment with siRNA is one of the current research hotspots for blocking the burst release of inflammatory cytokines in the NLRP3-mediated pyroptosis. PEI (polyethylenimine) combined with cholesterol (Chol) as the hydrophobic component has been discovered to be an excellent carrier for gene delivery due to its high transfection efficiency and low cytotoxicity. Ye et al. (64) assembled synthetic PEI-Chol (cholesterol grafted polyethylenimine) with GSDMD small interfering RNA (siRNA) to form PEI-Chol/siGSDMD polyplexes, and demonstrated the role of siGSDMD-loaded PEI-Chol in MSU-induced pyroptosis and acute inflammatory cascade, offering a potential therapeutic strategy for molecular treatment of acute GA.

DNA polymerase β (Polβ) has an important role in autoimmunity, and DNA damage caused by Polβ deficiency can induce RA macrophage pyroptosis, thereby aggravating the severity of the disease (58). Gu et al. (58) discovered that Pol β controls RA by suppressing macrophage pyroptosis through the cGAS/STING/NF-κB pathway. This finding strongly supports the significant involvement of Pol β in the advancement of RA, indicating its potential as a viable target for preventing and treating RA and related autoimmune disorders.

Zinc finger protein A20 plays a role in promoting cell proliferation and inflammatory response, and is involved in the regulation of the body’s innate and adaptive immunity. The A20 gene is strongly associated with the development of numerous inflammatory diseases. Walle et al. (43) discovered that A20 hinders the activation of NLRP3 inflammasome by decreasing the levels of NLRP3 expression. Consequently, the etiology of arthritis in A20myel-KO mice is attributed to the excessive activation of NLRP3 inflammasome. A20 is a novel negative regulator of NLRP3 inflammasome activation, and targeting A20 expression may provide a new strategy for the treatment of inflammatory bone diseases such as rheumatoid arthritis.