The activity of nuclear factor kappa-B (NF-κB) can be inhibited by estrogen and the zinc finger protein. In addition, zinc finger protein and aromatic hydrocarbon receptors can bind to exogenous chemical response elements on NLRP3 (Hajikhezri et al., 2020). Endogenous miR-233, which is highly expressed in the myeloid lineage, and mir-BART15, secreted by B cells after EB virus infection, can bind to the 3′untranslated end of NLRP3 mRNA, making it a target for degradation, accelerating its degradation, and negatively regulating NLRP3 inflammasome at the translational level (Yang et al., 2015).

Depending on the structure of the inflammasome, the central molecule usually contains the pyrin domain-caspase activating and recruitment domain region (Martinon et al., 2009; Davis et al., 2011). Proteins in this domain competitively bind to these molecules, thereby inhibiting the assembly of complexes. NLRP3 complex assembly is negatively regulated by proteins with a pyrin domain, which interferes with the signal transduction between ASC and NLRP3 (Martinon et al., 2009). Another class contains caspase recruitment domains such as only proteins, caspase-12, and other molecules, which inhibit NLRP3 activation by competitively binding to ASC with caspase-1. In addition, the protease inhibitor PI-9 can suppress the caspase-1 activation by competitively binding to the active site of caspase-1 (Kannan-Thulasiraman and Shapiro, 2002). The small heterodimer partner is recruited to mitochondria upon activation to bind NLRP3 competitively with ASC and inhibit NLRP3 inflammasome complex assembly (Yuk et al., 2016).

NLRP3 inflammasome activation methods vary, making the negative control of this pathway’s activation even more difficult to understand. Negative regulation of the NLRP3 inflammasome activation pathway is more complex due to the diversity of activation mechanisms. The cells can reduce their content of damaged mitochondria and ROS by activating the autophagy pathway under stress, thus negatively regulating NLRP3 activity (Zhou et al., 2011). Some substances, such as in vivo metabolites such as β-hydroxybutyric acid, can prevent intracellular K⁺ efflux to reduce ASC oligomerization and spot formation, negative regulation of NLRP3 inflammasome (Rayamajhi and Miao, 2013). In some autoimmune diseases, phospholipase C gamma 2 mutations enhance phospholipase Cγ2 activity, promote intracellular Ca2+ release from the endoplasmic reticulum, and activate the NLRP3 inflammasome (Chae et al., 2015).

Autophagy, which involves the breakdown and recycling of damaged cells, tissues, and organs, may intensify the inflammatory response (Morimoto and Cuervo, 2009). In autophagy, damaged cell tissues and organs are degraded and recycled (Basisty et al., 2018). Inflammatory reactions can be further exacerbated by the loss of autophagy-related proteins. Stress can inhibit mitochondrial damage and reduce ROS production through autophagy, which inhibits NLRP3 activation (Brookes et al., 2004). Nakahira et al. found that the loss of autophagy protein microtubule-associated protein light chain 3B (LC3B) and Beclin 2 expression was silenced, which activated caspase-1 and caused high expression of IL-18 and IL-1β, suggesting that the possible mechanism is impaired autophagy and mitochondrial dysfunction further activates NLRP3 inflammasome (Nakahira et al., 2011). Zhong et al. reported that NF-κB activation induced by LPS may lead to a further increase in p62/Sequestosome 1 expression, suggesting mitochondrial autophagy can negatively control p62/Sequestosome 1 expression (Zhong et al., 2016). The above shows that NLRP3 inflammasomes can be negatively regulated by mediating mitophagy.

Pineapple leaf polyphenols, which are organic phenol extracts from pineapple leaves, have lipid-regulating, antioxidant, and anti-diabetic properties (Xie et al., 2014). NF-κB plays an important role in many physiological processes, including inflammation. NF-κB is activated when lymphocytes are activated and differentiated, as well as when innate cells produce pro-inflammatory cytokines. During the inflammasome activation process, NF-κB initiates the transcription of NLRP3 and Pro-IL-1β components (Xu et al., 2022). The PLPs inhibit both NF-κB activation and proinflammatory molecule production such as pro-IL-1β, thus reducing the inflammatory response in mice colonic caused by DSS(Chen et al., 2021). As opposed to other secreted proteins, IL-1β normally requires secondary proteolytic cleavage by the NLRP3 inflammasome to activate and release. By preserving epithelial integrity, PLPs also prevent acute colitis caused by DSS.

RA(C₁₈H₁₆O₈) is abundant in plants of the Lamiaceae and Lithaceae families. It is known to have many biological effects, including antiviral, anti-inflammatory, and antibacterial (Mishra et al., 2021). By regulating the NLRP3 inflammasome and restoring the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway, RA nanovesicles may protect the colonic mucosa from damage caused by DSS(Marinho et al., 2021). Consequently, this formulation may offer a cutting-edge nutraceutical approach to treating UC in the oral cavity.

There is a natural non-flavonoid polyphenol in grapes and wine called resveratrol (C₁₄H₁₂O₃). The use of resveratrol (and its derivatives) for the treatment and prevention of numerous chronic diseases has shown promise, such as IBD and diabetes (Kitada et al., 2011). Several lines of evidence suggest that resveratrol reduces intestinal inflammation and damage (Dong et al., 2013). Research has shown that resveratrol inhibits the RAC-alpha serine/threonine-protein kinase (AKT1) and NLRP3 inflammasome in cardiomyocytes caused by acute sympathetic stimulation (Wang et al., 2022). According to the research in the animal model of radiation-induced IBD, resveratrol inhibits the expression of IL-1β and the NLRP3 inflammasome, which in turn reduces the expression of IL-1β and its synthesis and secretion (Sun et al., 2020). Resveratrol upregulated HO-1 to protect CaCO₂ from H₂O₂-induced oxidative damage and elevated epithelial expression of Occluding and zonula occludens (ZO)-1 in a dose-dependent manner (Wu et al., 2016). Resveratrol, however, also had effects on CaCO₂ cells that inhibited growth and stopped the cell cycle (Liu et al., 2014).

Traditional Chinese herbs such as Scutellaria baicalensis Georgi contain a bioactive flavonoid called baicalein (C₁₅H₁₀O₅), a flavonoid with bioactive properties (Kim et al., 2013). It was found that the TLR4/MyD88 pathway was significantly involved in the TNBS-induced production of pro-inflammatory cytokines and mediators, as well as downstream signaling molecules NF-κB and MAPKs, while NLRP3 was necessary for IL-1β release. The TLR4/MyD88 signaling cascades (NF-κB and MAPK) in lipopolysaccharide (LPS)-stimulated macrophages were downregulated by baicalein. The binding of baicalein to the hydrophobic area of the MD-2 pocket prevented the upstream development of the LPS-induced MD-2/TLR4 complex. Further, baicalein dose-dependently reduced downstream IL-1 expression and NLRP3 inflammasome activation. Baicalein suppressed TNBS-induced colitis, at least in part, by inhibiting TLR4/MyD88 signaling and inactivating the NLRP3 inflammasome (Luo et al., 2017).

Glycyrrhiza uralensis Fisch is a natural sweetener and herbal remedy for inflammatory illnesses (Yang et al., 2017). TFGU cures UC in mice by acting as an antioxidant through the Nrf2 pathway and as an anti-inflammatory through the NF-κB pathway. TFGU contains liquiditigenin, isoliquiritigenin, liquiritin, and glycyrrhizin, which are believed to be the main active ingredients of G. uralensis (Liu et al., 2018). The Toll-like receptor 4/myeloid differentiation protein 2 complex may be altered by isoliquiritigenin and glycyrrhizin at the receptor level, suppressing the signaling cascade and cytokine production. Additionally, liquiritigenin, isoliquiritigenin, and isoliquiritin may suppress the inhibitor of NF-κB (IκB) degradation and mediate anti-inflammatory responses induced by LPS(Cui et al., 2017). It is significant that isoliquiritigenin is predominantly found in the gastrointestinal tract and has the potential to reduce the severity of dextran sulfate sodium-induced colitis by inhibiting the MAPK pathway (Choi et al., 2016) and preventing colitis-related tumors by preventing the polarization of macrophage M2 by prostaglandin E2 and interleukin-6 (IL-6). As uric acid activates the NLRP3 inflammasome and releases inflammatory mediators such as IL-1β and IL-18, it contributes to inflammatory diseases (Martinon et al., 2006). Increased uric acid produced by an inflammatory reaction in the colon may worsen intestinal illness. When IBD mice were treated with uric acid alone, the condition was aggravated, and intestinal permeability was raised (Chiaro et al., 2017). This study found that TFGU suppressed the activation of the NLRP3 inflammasome in mice with colitis caused by irinotecan. When TFGU therapy was administered to colitis animals, purine metabolism was downregulated, which resulted in a significant decrease in fecal uric acid. As a result of these results, it appears that TFGU’s therapeutic action on irinotecan-induced gastrointestinal damage relies upon a reduction in fecal uric acid and suppression of the NLRP3 inflammasome (Yue et al., 2021).

Lonicerin (C₂₇H₃₀O₁₅), a flavonoid glycoside found in the flowers of Lonicera japonica Thunb., was commonly mentioned in ancient East-Asian prescriptions for treating inflammatory and infectious diseases (Shang et al., 2011). Several studies have shown that lonicerin has anti-inflammatory and immunomodulatory properties (Lee et al., 1995). Lonicerin increases autophagy to inactivate the NLRP3 inflammasome. According to a study, Lonicerin targets enhancers of zeste homolog 2 to reduce the symptoms of UC in mice by inactivating the NLRP3 inflammasome (Lv et al., 2021). By encouraging NLRP3 degradation to prevent NLRP3 inflammasome assembly, this work demonstrated that lonicerin selectively suppressed NLRP3 inflammasome activation in colonic macrophages. Subsequent research demonstrated that lonicerin improved autophagy to inactivate NLRP3 inflammasome.

Formononetin (C₁₆H₁₂O₄) is an isoflavone compound found in many natural plants. Astragalus, for example, contains this compound as one of its main biologically active components (Machado Dutra et al., 2021). Over 2000 years ago, astragalus was used in China to cure diabetes. Formononetin has been shown to have anti-inflammatory, antioxidative, antitumor, and promoting apoptosis properties in recent studies (Ma et al., 2013; Li et al., 2014; Lima Cavendish et al., 2015). It has been reported that formononetin reduces inflammation in rats with peritonitis and protects mice from acute lung damage caused by LPS (Ma et al., 2013). In vitro, formononetin reduced acute damage caused to colonic cells by TNF-α by selectively boosting tight junction protein expression. Meanwhile, formononetin reduced NLRP3 pathway protein levels in vivo and in vitro (NLRP3, ASC, IL-1β) (Wu et al., 2018).

The chemical molecule oroxindin (C₂₂H₂₀O₁₁) is a flavone and a phenolic compound. Specifically, it is a wogonoside, or wogonin glucuronide, which was isolated from Holmskioldia sanguinea, Oroxylum indicum, and Bacopa monnieri (all Bignoniaceae) (Fong et al., 2019). It was discovered that Huang-Qin (one of the key ingredients of Huang-Qin-Tang) contains a natural bioflavonoid called oroxindin. Studies have shown that oroxindin has anti-inflammatory, anti-tumor, and anti-oxidant properties (Wang et al., 2017). Researchers found that oroxindin reduces inflammation in the colon by inhibiting the formation and activation of the NLRP3 inflammasome, which is connected to its inhibitory effects on the TXNIP-dependent NF-κB signaling pathway (Liu et al., 2020).

Alpinetin (C₁₆H₁₄O₄) is a flavonoid found in ginger as well as large amounts of cardamom, turmeric, and tulip. There are a variety of health benefits associated with alpinetin, including antibacterial, antioxidant, anticancer, antithrombotic, hypotensive, hypolipidemic, hypoglycemic, antiemetic, and analgesic properties (Wikan et al., 2022). Alpinetin has been shown in earlier investigations to have protective properties against acute lung damage and mastitis in mice (Chen et al., 2013). A study found that alpinetin significantly reduced TNF-α and IL-1β production in mice, MPO activity, diarrhea, colonic shortening, and histological damage. In vitro, alpinetin significantly reduced the production of proinflammatory cytokines TNF-α and IL-1β induced by NF-κB and NLRP3 inflammasomes (He et al., 2016).

Procyanidin is a flavonoid found primarily in green tea, grape skin, and grape seeds. It has been demonstrated that procyanidin absorbs oxygen radicals at a rate that is substantially greater than that of vitamin C and vitamin E (Ariga, 2004). Additionally, procyanidin has been shown to treat a wide range of inflammatory conditions (Pallarès et al., 2013). Procyanidin inhibited DSS-induced acute colitis in C57BL/6 mice by downregulating matrix metalloproteinases 9 expression, inhibiting the NF-κB signaling pathway, limiting NLRP3 inflammasome formation, and decreasing macrophage IL-1β levels (Chen et al., 2017).

Kae (C₁₅H₁₀O₆) is the primary active ingredient of many therapeutic plants. Additionally, Kae has antitumor and antioxidant properties in addition to its capacity to facilitate neurological recovery (Kumar, 2020). As well as reducing inflammation in mice caused by LPS, Kae is also capable of reducing HMGB1/TLR4 pathway-induced inflammation (Rajendran et al., 2014). Furthermore, Kae inhibits advanced glycation end products, which are responsible for NF-κB and NADPH oxidase expression. Also, Kae may reduce LPS/ATP-induced inflammation in cardiac fibroblasts by lowering the release of inflammatory proteins such as IL-6, IL-1β, and TNF-α(Hung et al., 2017). An additional clinical trial showed lower serum levels of C reactive protein, TNF-α, and IL-6 in type-2 diabetics who ate a Kae-rich diet. Kae-rich diets also reduced the generation of inflammatory mediators, leading to wound healing in mice with colitis. Kae modulated immune function in UC animal models by modifying the gut microbiota and different metabolites. Also, Kae reduced the activation of TLR4 to NF-κB induced by LPS in vitro (Qu et al., 2021).

PF(C₂₃H₂₈O₁₁), a monoterpene glycoside, is derived from the radices of Paeoniae lactiflora Pall, which have been used extensively in China for medicinal purposes for around 1,200 years (Sun et al., 2012; Yu et al., 2019). PF serves as an anti-cancer and anti-inflammatory agent (Lu et al., 2014), and clinical trials using PF or total glucosides of paeony have shown that PF can reduce the symptoms of IBD and inflammatory illnesses (Zhou et al., 2020). Reports indicate that PF prevents chemically induced colitis by reducing inflammation (Zhang et al., 2014)and modifying gut microbial metabolism (Fan et al., 2020). In Chinese medicine, the roots of plants in the Paeonia genus, including Paeonia lactiflora Pall., have been used to treat conditions similar to UC. Researchers examined the therapeutic effects of PF on mice with DSS-induced colitis discovering that PF had a preventative effect on colitis. With the PF treatment, activation of the NF-κB pathway was suppressed, reducing pro-inflammatory factor expression (Li et al., 2021).

The root extracts of the three-wingnut and thunder god vine, Tripterygium regelii, contain a substance called celastrol (tripterine) Celastrol (C₂₉H₃₈O₄) belongs to the quinone methides family of Pentacyclic Nortriterpene Quinones (Corson and Crews, 2007; Shi et al., 2020). The research shows that treatment with celastrol attenuated DSS-induced colon shortening and neutrophil infiltration. Besides, celastrol ameliorated DSS-induced colon injury and inflammatory signs as visualized by histopathology (Shaker et al., 2014). In the mouse model of DSS-induced colitis, celastrol prevents intestinal epithelial homeostasis loss by ameliorating acute intestinal injury. NLRP3 inflammasome, IL-23/IL-17 pathway, inflammatory cytokines, neutrophil infiltration, and E-cadherin expression are all inhibited by CSR, which suppresses colonic oxidative stress (Shaker et al., 2014; Jia et al., 2015).

Asiatic acid (C₃₀H₄₈O₅) is a natural triterpenoid molecule found in Centella Asiatica and Terminalia catappa, which is used in both Indian Ayurvedic and Chinese medicine (Tang et al., 2006; Huang et al., 2011). C. asiatica extract is usually used for medicine, tea, or aesthetic purposes (Bylka et al., 2013). In previous studies, asiatic acid has been demonstrated to have anti-inflammatory, neuroprotective, antioxidant, and anti-cancer properties (Gao et al., 2004; Zhang et al., 2012). Studies have shown that asiatic acid targets the NLRP3 inflammasome to treat UC(Guo et al., 2015). In this study, DSS-induced UC in mice significantly reduced the symptoms of colitis. Its mechanism involves inhibiting the ROS-NLRP3-caspase-1-IL-1β cascade in macrophages.

CA (C₂₀H₂₈O₄) is an alkane diphenol diterpene found in rosemary, therapeutic sage, and other plants. Rosemary extract has two main active ingredients, CA and carnosol, which are antioxidants and preservatives. It has been reported that 300 μg/mL rosemary leaf extract (89 mg/g carnosic acid) can inhibit the level of reactive oxygen species in the liver, brain, and stomach of rats and the lipid peroxidation products induced by sodium ferricyanide (Amaral et al., 2019). Studies have shown that CA in DSS-induced UC mice significantly prevented weight loss and colon length shortening in colitis improved the obvious infiltration of immune cells and the loss of crypt structure and goblet cells and explored its mechanism. It was found that CA significantly reduced MPO activity and F4/80⁺ macrophage infiltration in colon tissue, reduced the activation of p65 and c-Jun signals, and reduced caspase 1 activity to induce NLRP3 inflammasome activation (Yang et al., 2017).

Lib M is the first diterpene of the pimarane type isolated from the marine fungus Stibella fimetaris. In plants, fungi, and marine animals, pimarane diterpenes are important tricyclic diterpenes (Kildgaard et al., 2017). A variety of biological functions are demonstrated by them, including anti-inflammatory properties (Costantino et al., 2009). Studies have shown that Lib M has strong anti-inflammatory activity by inhibiting the nuclear translocation of NF-κB and the assembly of the NLRP3 inflammasome in activated macrophages. In this study, it was found that Lib M can effectively alleviate the symptoms of colitis in the DSS-induced UC mouse model, indicating that Lib M has a reasonable therapeutic prospect as a UC drug targeting NLRP3 (Fan et al., 2020).

Ginsenoside is a sterol compound, a triterpenoid saponin. It is only found in ginseng plants. Ginsenosides are regarded as the active ingredients in ginseng and thus become the target of research. Because ginsenosides affect multiple metabolic pathways, their efficacy is also complex, and the efficacy of various ginsenosides is difficult to isolate (Table 4).

Dioscin (C₄₅H₇₂O₁₆) is a natural steroidal saponin isolated and purified from the family Dioscoreaceae. Dioscin has excellent activity in metabolism, anticancer, anti-inflammation, and oxidative stress (Tao et al., 2018). Recent studies have found that dioscin can reduce serum uric acid levels and enhance uric acid excretion (Zhang et al., 2018). In addition, dioscin can improve atherosclerosis caused by hyperuricemia, inhibit the activation of the NF-κB signaling pathway, and the production of inflammatory cytokines to reduce the inflammatory response of gouty arthritis (Han et al., 2021). In UC-related experiments, studies have explored the role of Dioscin in DSS-induced UC. Dioscin can be effective in inhibiting DSS-induced colitis NF-κB, MAPK signaling, and NLRP3 pathway (Cai et al., 2021). These results suggest that Dioscin is a candidate drug for future treatment of UC.

Pectic polysaccharides, a class of heteropolysaccharides rich in 1,4-galacturonic acid, are mostly composed of galactose, galactose, arabinose, and rhamnose. A study found that pectic polysaccharides prevented UC in mice (Fan et al., 2020; Chen et al., 2022). Traditional Chinese medicine Smilax China L. has been found to contain a new type of pectin polysaccharide SCLP3-2. It was found that SCLP had anti-inflammatory properties in vitro (Zhang et al., 2019). Researchers have demonstrated that SCLP can effectively improve DSS-induced acute UC by binding to Gal-3 and inhibiting its activity, thus blocking NLRP3 inflammasome signaling, indicating that SCLP may be an effective candidate drug to prevent and treat UC(Pan et al., 2022).

APS (C₁₀H₇ClN₂O₂S) is a major component of Astragalus membranaceus, widely used in Chinese medicine and clinical research. Astragalus polysaccharide has immunomodulatory, anti-tumor, anti-lipid, anti-heart failure, and antioxidant effects (Cho and Leung, 2007; Lee et al., 2007). A TNBS-induced rat model of colitis was substantially reduced by APS through its control of cytokine expression, according to studies (Yang et al., 2014). Furthermore, Astragalus and Lycium barbarum L. (Solanaceae) polysaccharides help the intestinal barrier heal and protect against experimental UC(Zhao et al., 2014). APS can also downregulate the expression of NLRP3, caspase-1, and ASC in colon tissue, prevent the activation of the NLRP3 inflammasome, thereby reducing the expression of IL-18 and IL-1β and alleviating DSS-induced colon inflammation (Tian et al., 2017).

Sinapic acid (C₁₁H₁₂O₅) is a naturally occurring hydroxycinnamic acid commonly found in fruits, vegetables, grains, and oilseed crops. It is also found in wine and vinegar (Chen and longevity, 2016). Sinapic acid exhibits a variety of pharmacological effects, including antibacterial, anticancer, anti-inflammatory, anticancer, antimutagenic, antiglycemic, and antioxidant properties. A study by Lee has shown that TNBS-induced colitis is capable of reducing inflammation in mice (Lee, 2018). Sinapic acid also reduced the signs of DSS-induced colitis in mice by controlling NLRP3 inflammasome. DSS-induced mice treated with Sinapic acid had significantly decreased levels of NLRP3, IL-1b, ASC, and Caspase-1, which improved symptoms of colitis (Qian et al., 2020).. (Table 4)