Targeting inflammasome in digestive diseases: A dual approach of Western and Chinese medicine

Abstract

The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a key innate immune complex regulating inflammation and homeostasis. Its aberrant activation drives caspase-1 and interleukin-1β/interleukin-18 maturation, fueling excessive inflammation. Dysregulated NLRP3 signaling is closely linked to digestive diseases including inflammatory bowel disease, acute pancreatitis, and nonalcoholic fatty liver disease, exacerbating barrier dysfunction, tissue injury, and hepatic inflammation. Western medicine strategies target inflammasome assembly, upstream signals, or downstream cytokines; several inhibitors show anti-inflammatory effects in models and early trials, but to date no NLRP3 inhibitor has been approved by the United States Food and Drug Administration for digestive diseases, and face challenges in long-term safety and specificity, with several candidate drugs failing in clinical trials due to hepatotoxicity or poor efficacy. Traditional Chinese medicine (TCM) can affect several targets and pathways. Recent research indicates that TCM components and prescriptions control the activation of NLRP3 via oxidative stress, immune unbalance and inflammatory pathways, providing extra benefits. Therefore, the NLRP3 inflammasome provides an encouraging treatment connection between innate immunity and digestive diseases. Further research should combine Western and TCM mechanisms, increase the clinical evidence and promote translational studies for accurate therapies.

Key Words: NOD-like receptor family pyrin domain-containing 3 inflammasome; Digestive system diseases; Inflammation; Traditional Chinese medicine; Therapeutic target; Pyroptosis; Gut-liver axis

Core Tip: The activation of NOD-like receptor family pyrin domain-containing 3 inflammasome is connected with some digestive system diseases through inflammation and pyroptosis. At present, Western medicine focuses on this problem, but no inhibitor has been used in digestive diseases and some serious side effects (such as hepatotoxicity) also occur, together with unsuccessful clinical trials. On the contrary, traditional Chinese medicine regulates it from various aspects. A combined therapy involving both traditional Chinese medicine and Western medicine may exhibit an additive effect and provides a promising precise therapeutic approach for digestive disorders.

INTRODUCTION

Diseases of the digestive system are a major public health problem worldwide, involving various clinical conditions such as acute and chronic inflammatory diseases, intestinal infections, hepatobiliary diseases, pancreatitis and gastrointestinal cancers. According to the Global Burden of Disease database, 7.32 billion cases of digestive system diseases were recorded in 2019, influencing about 2.86 billion people and causing 8 million deaths and a total of 277 million disability-adjusted life years lost. These diseases take up a considerable part of the global disease burden, showing significant regional differences[1]. In addition to the serious mortality risk, the long-term inflammatory processes related to digestive diseases are connected with reduced living standards, increased consumption of health care resources and systemic metabolic disorders. For instance, the prevalence of inflammatory bowel disease (IBD) remains constant (0.5% to 1.0%) in high-income countries whereas it increases markedly in newly developed regions[2]. At the same time, the incidence of malignant conditions like metabolic dysfunction-associated steatotic liver disease (MASLD), hepatocellular carcinoma and pancreatic cancer is increasing all over the world, which leads to more clinical and public health problems[3].

The innate immune system plays a role in the first line of defense against pathogens and endogenous danger signals, where inflammasomes are important multi-protein structures which detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), thus triggering subsequent pro-inflammatory responses[4]. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is one of the most extensively studied inflammasome subtypes and is assembled from the intracellular pattern recognition receptor NLRP3, adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. Its activation requires a two-step process: A priming signal [e.g., Toll-like receptor (TLR)-mediated upregulation of NLRP3 and pro-interleukin (IL)-1β/pro-IL-18 expression via the nuclear factor kappa B (NF-κB) pathway] and an activation signal (e.g., K⁺ efflux, mitochondrial stress, and lysosomal rupture)[5]. Upon activation, the NLRP3 inflammasome facilitates the autocleavage and maturation of caspase-1, which in turn promotes the maturation and secretion of IL-1β and IL-18, while concomitantly inducing pyroptosis. Thus, it plays a central role in the inflammatory response and tissue injury[6,7].

Accumulating evidence has confirmed the pivotal role of the NLRP3 inflammasome in the pathophysiology of various digestive system diseases. In patients with IBD, the expression levels of NLRP3, caspase-1, and IL-1β are significantly elevated and are correlated with disease activity[8,9]. Moreover, the abnormality of inflammasome signaling is related to Helicobacter pylori-induced gastritis, acute and chronic pancreatitis, hepatic inflammation and fibrosis[10]. Moreover, it has been found that inflammasomes not only play a role in keeping the intestinal microecological balance and regulating the interaction between microbiota and immune system, but also have complicated functions in the tumour immune microenvironment and during the onset and development of the disease[11].

Due to the important position of the NLRP3 inflammasome in innate immunity and chronic inflammation-related diseases, various therapeutic approaches focusing on its signaling pathway have been paid attention to in the field of digestive system diseases. In Western medicine, main efforts are directed towards the creation of small molecule inhibitors, biological agents and upstream pathway regulators to prevent excessive activation of the inflammasome or inhibit the release of IL-1β/IL-18. However, some problems still exist concerning their safety, specificity and clinical application. Traditional Chinese Medicine (TCM) with its multi-target and multi-pathway regulatory features has shown the ability to synergistically modulate the inflammasome signaling network in experimental models. Combining the recent research findings and the underlying mechanisms can further clarify the immunoinflammatory mechanisms mediated by the NLRP3 inflammasome in digestive diseases, offering a theoretical and practical foundation for the integration of TCM and Western medicine strategies, which is beneficial to the improvement of precise and efficient treatments. The purpose of this paper is to give a scientific basis for the NLRP3 inflammasome as a significant therapeutic target in digestive system diseases and to compare the similarities, differences, and advantages of TCM and Western medicine intervention strategies, and offer references and directional guidance for future innovative drug development and integrated precision therapy based on this target.

NLRP3 INFLAMMASOME OVERVIEW

The NLRP3 inflammasome is a cytoplasmic multi-protein complex which plays an important role in the innate immune system's monitoring and regulation of inflammation. It contains the NLRP3 sensing protein, the adapter protein ASC and the effecting substance pro-caspase-1[12-14]. Among the identified inflammasomes, NLRP3 has been investigated more in detail due to its reactions to different endogenous and exogenous danger signals and its connection with inflammatory diseases[15]. Regarding its structure, NLRP3 comprises three functional regions: (1) The N-terminal pyrin domain (PYD); (2) The central NACHT domain which is involved in oligomerization; and (3) The C-terminal leucine-rich repeat domain which is related to ligand recognition and auto-regulation[16]. When recognizing the PAMPs or DAMPs (such as microorganisms, extracellular ATP, crystalline substances, mitochondrial dysfunction products and ionic changes), NLRP3 experiences conformational changes and oligomerization[17-19]. The activated NLRP3 associates with ASC via homotypic PYD-PYD interactions and ASC subsequently binds pro-caspase-1 by CARD-CARD interactions, leading to the formation of the inflammasome complex[20].

Activation of the NLRP3 inflammasome usually needs a two-step process which includes a priming and an activating signal. The priming stage is mainly carried out by pattern recognition receptors such as TLRs, which induce the activation of NF-κB signalling and enhance the transcription of NLRP3 and its pro-inflammatory cytokine precursors (pro-IL-1β and pro-IL-18)[21,22]. The following activating signal is caused by various cellular stress conditions like potassium efflux, calcium influx, production of reactive oxygen species (ROS), mitochondrial injury and lysosomal disruption, finally leading to the formation of the inflammasome and the activation of caspase-1[23-25].

After assembly, the NLRP3 inflammasome causes the autocatalytic cleavage of pro-caspase-1 into its active form. The activated caspase-1 converts pro-IL-1β and pro-IL-18 into mature and biologically active cytokines which are released quickly and stimulate both local and systemic inflammatory responses[26,27]. In addition, caspase-1 cleaves gasdermin D, leading to the formation of membrane pores and induction of pyroptosis, a form of inflammatory programmed cell death which helps in pathogen elimination, but may cause tissue damage if not properly controlled[28,29].

Physiologically, the activation of the NLRP3 inflammasome is necessary for the defence of the host against infections and the maintenance of immune balance. It has been found that the excessive or uncontrollable activation of the inflammasome is connected with some pathological conditions. There is enough evidence indicating that the abnormal signal of the NLRP3 inflammasome is related to autoinflammatory diseases (such as cryopyrin-associated periodic syndromes) and metabolic disorders including type 2 diabetes mellitus, obesity, atherosclerosis and gout[30-32]. These results emphasize the significant role of NLRP3 inflammasome as the main molecular link between metabolic stress, immune unbalance and chronic inflammation.

Due to its wide participation in inflammatory and metabolic diseases, the NLRP3 inflammasome has been recognized as an important therapeutic site. Studying its molecular structure, activation processes and the following effects will serve as a fundamental basis for clarifying its function in digestive system diseases which include continuous inflammation, immunological disorder and tissue destruction. This theoretical framework prepares for further discussion about the pathological effect of NLRP3 inflammasome activation in digestive disorders and the possibility of medical treatments, both western and based on TCMs, acting on this pathway.

PRIMING AND ACTIVATION MECHANISMS OF THE NLRP3 INFLAMMASOME

Activation of the NLRP3 inflammasome is a process which involves several steps and is regulated by transcriptional priming, post-translational modifications and various cellular stress signals, to start the innate immune responses. Previously, the NLRP3 inflammasome activation needs a priming step (signal 1) and an activation step (signal 2); nevertheless, recent studies show that there are non-canonical and alternative activation pathways also exist, indicating the complexity and the dependence on the context of NLRP3 signaling.

The priming process is important for making cells capable of NLRP3 inflammasome activation and is mainly controlled by NF-κB signaling. The activation of pattern recognition receptors (such as TLRs) or cytokine receptors (such as tumor necrosis factor receptor) results in the nuclear translocation of NF-κB and the subsequent transcriptional increase of NLRP3, pro-IL-1β and pro-IL-18[33]. In addition, NF-κB signaling participates in the post-translational regulation of NLRP3 (including phosphorylation and ubiquitination), thus reducing the activation threshold of inflammasome[34].

In addition to the classical inflammatory signal, some apoptotic related substances take part in the priming of inflammasome. Caspase-8 has a dual regulatory role on the NLRP3 signal: It enhances the expression of cytokines via the NF-κB pathway, but restrains excessive inflammasome activation under certain conditions[35]. The Fas associated death domain protein acts as a molecular scaffold connecting the death receptor signal to the priming of inflammasome, which indicates the interaction between the apoptotic and inflammatory pathways during the regulation of NLRP3[36].

Perturbation of intracellular ion balance is important for activating the NLRP3 inflammasome. The release of potassium (K⁺) is one of the key steps in the canonical activation of NLRP3 and can be triggered by extracellular ATP through the activation of P2X7 receptor, pore-forming toxins or membrane damage[37]. A reduction in intracellular K⁺ concentration will result in conformational changes in NLRP3 and induce its association with the serine/threonine kinase NEK7, which is necessary for the formation of the inflammasome[38]. It needs to be pointed out that the efflux of K⁺ and the generation of ROS have a regulatory interaction on NLRP3 activation: The efflux of K⁺ enhances mitochondrial ROS production by disturbing the mitochondrial membrane potential, and the accumulated ROS causes thioredoxin-interacting proteins (TXNIP) to dissociate from thioredoxin and bind to NLRP3, forming a positive feedback loop which strengthens the inflammasome activation. Besides, the influx of sodium (Na⁺) and the efflux of chloride (Cl^-) also take part in the activation of NLRP3 by means such as mitochondrial dysfunction and the secondary amplification of inflammatory signals[39]. The changes in membrane potential, osmotic equilibrium and mitochondrial stability brought about by the influx of Na⁺ and the efflux of Cl^- promote the oligomerization and activation of NLRP3[40].

Generation of ROS and mitochondrial dysfunction are also significant in the NLRP3 signaling pathway. Certain stimuli of inflammasome can induce the production of ROS in mitochondria, forming a danger signal between the cellular stress and the activation of innate immunity[41]. ROS can cause TXNIP to separate from thioredoxins, so that TXNIP can directly interact with NLRP3 and promote the activation of inflammasome[42]. Furthermore, mitochondrial damage results in the release of oxidized mitochondrial DNA and cardiolipin, which are associated with NLRP3 and strengthen the assembly of inflammasome[43]. Another way to activate the NLRP3 inflammasome is by the phagocytosis of particulate or crystalline substances (such as monosodium urate crystals, silica or cholesterol crystals), leading to the release of cathepsins (especially cathepsin B) into the cytosol, which act as potent activators of the NLRP3 inflammasome[44]. This process is particularly important in sterile and chronic inflammatory diseases, where continuous exposure to particulates causes persistent lysosomal stress and inflammasome signaling.

In addition to the canonical caspase-1 dependent pathway, a non-canonical inflammasome activation process has also been found. In this route, cytosolic lipopolysaccharide (LPS) directly activates caspase-11 in mice or caspase-4/5 in humans, resulting in the cleavage of gasdermin D, pyroptosis and secondary K⁺ efflux, which then initiates the formation of NLRP3 inflammasome and activates caspase-1[45]. This non-canonical pathway shows special clinical importance in digestive system diseases. During acute pancreatitis (AP), the injury of acinar cells releases LPS intracellularly, which activates caspase-4/5 in human pancreatic tissues and causes large amounts of pyroptosis, thus aggravating pancreatic necrosis. In viral hepatitis B, the joint action of viral antigens and gut-derived LPS leakage activates the caspase-4/NLRP3 axis in hepatocytes, promoting persistent hepatic inflammation and accelerating fibrosis development. Furthermore, an alternative activation pathway has been described in human monocytes, wherein TLR4 signaling induces NLRP3-dependent IL-1β maturation through a caspase-8-dependent mechanism without robust K⁺ efflux or pyroptotic cell death[46].

Post-translational modifications can affect the activation of NLRP3 inflammasome. Phosphorylation, ubiquitination, SUMOylation and acetylation change the stability, subcellular location and interaction with adapter proteins of NLRP3[47]. These modifications occur during both the priming and activation stages, enabling the fine regulation of the inflammasome’s reaction and intensity to different inflammatory stimuli. The activation process of NLRP3 inflammasome is illustrated in Figure 1.

Figure 1 Canonical and non-canonical activation pathways of the NOD-like receptor family pyrin domain-containing 3. NLRP3: NOD-like receptor family pyrin domain-containing 3; TLR: Toll-like receptor; PAMPs: Pathogen-associated molecular patterns; DAMPs: Damage-associated molecular patterns; NF-κB: Nuclear factor kappa B; IL: Interleukin; PYD: Pyrin domain; LRR: Leucine-rich repeat; ROS: Reactive oxygen species; TXNIP: Thioredoxin-interacting proteins; LPS: Lipopolysaccharide.

ROLE OF THE NLRP3 INFLAMMASOME IN DIGESTIVE SYSTEM DISEASES

Several researches indicate that the activation of the NLRP3 inflammasome in an abnormal manner is crucial for the occurrence and progression of different digestive organ diseases. By recognizing metabolic stress, microbial substances and danger signals related to tissue injury, the NLRP3 inflammasome mainly regulates the inflammatory processes through the maturation of IL-1β and IL-18. The disturbance of NLRP3 signal transduction leads to chronic inflammation, destruction of epithelial barrier, immune imbalance and fibrosis in both liver and intestinal diseases[48,49].

NLRP3 inflammasome in MASLD and non-alcoholic steatohepatitis

MASLD and its advanced forms are linked to sterile inflammation caused by metabolic stress. Hepatocyte lipid accumulation, mitochondrial dysfunction, and oxidative stress generate DAMPs that activate the NLRP3 inflammasome in hepatocytes, Kupffer cells, and hepatic stellate cells[50-52]. Activated NLRP3 induces the caspase-1 dependent maturation of IL-1β and IL-18, which intensify hepatic inflammation by attracting immune cells and increasing the production of pro-inflammatory cytokines[53].

IL-1β induces insulin resistance, hepatocyte damage and fatty liver through activation of the downstream NF-κB pathway and chemokine secretion[54].

Though the action of IL-18 is different according to the conditions, it participates in hepatic inflammation and fibrosis when it is activated by NLRP3 signaling[55]. Moreover, the activation of the NLRP3 inflammasome disturbs the balance of the gut-liver axis by reducing the integrity of intestinal barrier, increasing gut permeability and promoting the translocation of microbial products (like LPS) into portal circulation, thus activating the hepatic TLR4-NF-κB pathways again[56-58]. Some preliminary clinical findings from small or medium-sized researches indicate that the NLRP3 mRNA expression in the liver tissues of MASLD patients is 3.2-5.7 times higher than that in normal people, and the peripheral blood IL-18 concentration has a positive correlation with the degree of hepatic fibrosis[59,60]. However, the fold changes obtained in various studies are not uniform and large-scale verification [for example, from the metabolic dysfunction-associated steatohepatitis (MASH) Clinical Research Network] is at present unavailable. Besides, there might be publication bias which could exaggerate the strength of these relationships. NLRP3 inflammasome activation in hepatic parenchymal and immune cells is a core driver of MASLD/MASH progression, mediating the transition from simple steatosis to inflammatory fibrosis by promoting IL-1β/IL-18 secretion and gut-liver axis dysfunction. Targeting NLRP3 or its upstream ROS/NF-κB signaling pathway represents a key direction for MASLD/MASH treatment.

NLRP3 inflammasome in viral hepatitis

In viral hepatitis caused by the hepatitis B virus or hepatitis C virus, persistent viral replication and immune-mediated hepatocyte injury trigger chronic inflammasome activation. Viral components and virus-induced cellular stress activate pattern recognition receptors (including TLR4), leading to NF-κB-dependent priming of NLRP3 and pro-inflammatory cytokines[61,62]. Subsequent NLRP3 inflammasome activation in hepatocytes and liver-resident immune cells promotes IL-1β and IL-18 secretion, which contribute to hepatic necroinflammation and disease progression[63]. Clinical studies have demonstrated that the positivity rate of NLRP3 protein in liver biopsy tissues of patients with chronic hepatitis B virus infection is as high as 78%, which is significantly higher than the 12% detected in healthy controls[64,65]. Given that this is a single-center observation with a modest number of participants, confirmation in independent, larger cohorts is necessary before generalizing these percentage values.

IL-18 exerts dual roles in viral hepatitis: It modulates antiviral immune responses while exacerbating tissue injury when overproduced. Sustained NLRP3 signaling is linked to enhanced hepatic fibrosis through activation of hepatic stellate cells and increased expression of transforming growth factor-β and extracellular matrix components[66]. The non-canonical caspase-4/NLRP3 pathway is also involved in disease pathogenesis. The non-canonical caspase-4/NLRP3 pathway is also involved in disease pathogenesis. In chronic hepatitis B, persistent viral replication and hepatocyte injury cause intracellular leakage of gut-derived LPS, which directly activates caspase-4 in human hepatocytes. Activated caspase-4 cleaves gasdermin D to induce pyroptosis, a highly inflammatory form of cell death, and simultaneously triggers secondary K⁺ efflux, thereby promoting NLRP3 inflammasome assembly and caspase-1 activation[67]. This caspase-4/NLRP3 axis amplifies hepatic necroinflammation and accelerates the progression of liver fibrosis. Viral infection-induced hepatocyte damage leads to LPS leakage, which activates caspase-4, induces pyroptosis, and amplifies NLRP3-dependent inflammation. Viral infection-induced hepatocyte damage leads to LPS leakage, which activates caspase-4, induces pyroptosis, and amplifies NLRP3-dependent inflammation. The NLRP3 inflammasome mediates the interaction between viral infection and hepatic inflammation in viral hepatitis, and its persistent activation accelerates the progression of liver fibrosis. Inhibition of both the canonical NLRP3/caspase-1 and non-canonical caspase-4/NLRP3 pathways is a potential strategy for alleviating chronic viral hepatitis injury.

NLRP3 inflammasome in ulcerative colitis

Beyond the canonical NLRP3/caspase-1 axis, emerging evidence indicates that caspase-8 plays a dual role in intestinal inflammation. On one hand, caspase-8 can act upstream of NLRP3 by promoting NF-κB-dependent transcriptional priming of NLRP3 and pro-IL-1β in response to microbial signals. On the other hand, in the setting of impaired caspase-8 activity [e.g., in certain Crohn’s disease (CD) patients with caspase-8 mutations], epithelial cells undergo RIPK3-dependent necroptosis, leading to exaggerated NLRP3 inflammasome activation and IL-1β release. Caspase-8 acts as a molecular rheostat to regulate inflammasome activation and cell death in the gut mucosa[68].

Ulcerative colitis (UC) is an inflammatory disease of the colon with impaired intestinal epithelial barrier function. The activation of the NLRP3 inflammasome has been found to be closely related to the development of UC. Intestinal epithelial cells and macrophages in the lamina propria recognize microorganisms and endogenous danger signals which activate the NLRP3 resulting in the release of IL-1β and IL-18[69,70]. Some limited clinical evidence from small groups of patients suggests that the mRNA expressions of NLRP3 and IL-1β in the colonic mucosa of active UC patients are 4.5-fold to 6.8-fold and 3.9-fold to 7.1-fold higher than those in healthy individuals respectively, and there is a positive correlation between NLRP3 levels and the Mayo score[71]. It should be pointed out that these fold ratios vary among different studies and have not been universally confirmed in all published data; therefore, more prospective multicenter studies are necessary to verify these quantitative relationships.

IL-1β induces neutrophil recruitment, increases vascular permeability and intensifies mucosal inflammation through NF-κB dependent pathway[72]. IL-18 is important in maintaining the integrity of epithelium and antimicrobial defence; nevertheless, the overproduction of IL-18 due to the excessive activation of NLRP3 disrupts the tight junction proteins and impairs epithelial regeneration, which ultimately worsens the barrier dysfunction[73,74]. Experimental colitis models indicate that the inhibition or genetic deletion of NLRP3, caspase-1 or IL-1β can alleviate colonic inflammation and restore the epithelial barrier integrity[75,76]. The overactivation of NLRP3 inflammasome in intestinal mucosa is a main cause of the damage in UC, intensifying the inflammatory infiltration and barrier dysfunction via IL-1β and IL-18. Therefore, targeting NLRP3 or blocking the downstream IL-1β/IL-18 signalling pathway is an effective way to reduce the activity of UC.

NLRP3 inflammasome in CD

CD includes transmural inflammation and immune dysfunction, influencing the whole gastrointestinal tract. Activation of the NLRP3 inflammasome is closely linked to microbial dysbiosis and defective mucosal immunity in CD. Altered gut microbiota composition increases exposure to PAMPs, activating TLR4-NF-κB signaling and priming the NLRP3 inflammasome[77,78]. Some clinical studies have reported that NLRP3 mRNA expression in the ileal mucosa of patients with CD is 2.8-fold to 4.1-fold higher than that of healthy individuals, and IL-1β levels in intestinal lavage fluid are significantly correlated with the severity of intestinal stenosis[79,80]. However, these findings are derived from relatively small sample sizes, and no large-scale collaborative study has yet validated specific cut-off values or fold-change thresholds for clinical use.

Activated NLRP3 promotes an imbalance between pro-inflammatory and anti-inflammatory cytokines by enhancing IL-1β production while suppressing regulatory immune responses (including IL-10 signaling). Excessive IL-18 production is associated with epithelial cell apoptosis and impaired mucosal healing in CD. Animal studies and patient-derived data indicate that controlled NLRP3 activation is required for host defense, whereas sustained or dysregulated activation drives chronic inflammation and tissue damage in CD[81-83]. The NLRP3 inflammasome is involved in immune imbalance and mucosal damage in CD, and its abnormal activation mediates an imbalance between pro-inflammatory/anti-inflammatory cytokines and impairs mucosal repair. Regulation of NLRP3 activation and restoration of the intestinal flora balance are key intervention targets for CD.

Additional digestive system disorders associated with NLRP3 inflammasome activation

In addition to liver diseases and IBD, NLRP3 inflammasome activation has been implicated in other digestive system disorders, including cholestatic liver disease, pancreatitis, and colorectal cancer. In a cholestatic condition, bile acids can cause cellular stress and activate the NLRP3 signaling, resulting in bile duct epithelial damage and fibrosis[84]. During pancreatitis, the destruction of acinar cells and the intracellular calcium overload can activate the NLRP3 inflammasome, which promotes inflammation through IL-1β[85]. Moreover, in human AP, the damaged acinar cells secrete intracellular LPS which directly activates caspase-4 (or caspase-5 in some cases). The activated caspase-4 cleaves gasdermin D, causing extensive pyroptosis and releasing DAMPs. These DAMPs can also activate the NLRP3 inflammasome in neighboring macrophages and stellate cells, forming a positive feedback loop between the non-canonical caspase-4 pathway and the canonical NLRP3/caspase-1 pathway, thereby intensifying pancreatic necrosis and systemic inflammation[86]. In addition, continuous cytokine secretion and immune imbalance are connected with the chronic inflammation induced by NLRP3 in colorectal cancer, which plays a role in the promotion of the tumor microenvironment[87,88].

RESEARCH INVESTIGATING INTEGRATED TCM AND WESTERN MEDICINE INTERVENTIONS FOR DIGESTIVE SYSTEM DISEASES BASED ON THE NLRP3 INFLAMMASOME

Many studies on the NLRP3 inflammasome have been carried out in both Western medicine and TCM. In Western medicine, particular inhibitors are mainly used, while in TCM, emphasis is laid on single herbs, classical prescriptions and herbal extracts with different characteristics.

Western medicine intervention research

In Western medicine, particular inhibitors are mainly used, while in TCM, emphasis is laid on single herbs, classical prescriptions and herbal extracts with different characteristics. The intervention study in Western medicine mainly concentrates on specific inhibitors and pathway modifiers, which show clear effects and high specificity towards the target.

Specific inhibitors of the NLRP3 inflammasome: MCC950 is an effective inhibitor for the NLRP3 inflammasome. It binds to NLRP3 and prevents its ATPase activity, thus stopping the production and activation of inflammasome. Studies have demonstrated that MCC950 can significantly reduce NLRP3 inflammasome activation levels in liver tissues of MASLD mice, decrease inflammatory factor secretion, and ameliorate hepatic steatosis and inflammatory injury. Furthermore, MCC950 alleviates pancreatic damage and reduces mortality in mouse models of AP by inhibiting the NLRP3 inflammasome[89-91]. In addition to MCC950, novel NLRP3 inhibitors such as CY-09 and OLT1177 have exhibited promising anti-inflammatory effects[92-94].

However, despite the promising preclinical antiinflammatory effects of these inhibitors, several important limitations must be acknowledged. First, to date, no NLRP3specific inhibitor has been approved by the United States Food and Drug Administration (FDA) for the treatment of any digestive system disease. Second, longterm safety concerns have emerged. For instance, MCC950 was found to induce hepatotoxicity in chronic toxicology studies, including elevated liver enzymes and hepatocellular necrosis in animal models, which halted its further clinical development for non-emerging indications. Third, clinical translation has faced multiple failures. The NLRP3 inhibitor AZD-007 (AstraZeneca) was discontinued in Phase I due to off-target cardiovascular effects. Similarly, a smallmolecule NLRP3 inhibitor developed by Inflazome (now Roche) failed to show sufficient efficacy in phase II trials for IBD[95]. These examples underscore that safety, target specificity, and efficacy in humans remain major hurdles for NLRP3-targeted therapies.

Pathway modulators: This class of drugs exerts their effects by regulating the upstream and downstream signaling pathways involved in NLRP3 inflammasome activation. For example, NF-κB pathway inhibitors (e.g., pyrrolidine dithiocarbamate) suppress NLRP3 inflammasome activation by inhibiting NF-κB activation and downregulating NLRP3 and pro-IL-1β expression[96-98]. ROS scavengers (including vitamin E and glutathione) inhibit NLRP3 inflammasome activation by reducing ROS production[99-101]. Lysosome stabilizers (e.g., chloroquine) block the lysosomal damage-mediated NLRP3 activation pathway by preserving lysosomal membrane integrity[102,103].

TCM intervention research

TCM has a long history and extensive use in the treatment of diseases of the digestive system. Its mechanisms of action are characterized by multi-target and multi-pathway regulation, complementing the targeted therapies of Western medicine. Recent studies have revealed that various Chinese herbs, classic formulas, and their extracts exert their therapeutic effects by regulating the NLRP3 inflammasome.

Single Chinese herbs and extracts: (1) Saikosaponin-d: Saikosaponin-d, one of the main active components of Bupleurum chinense DC, possesses anti-inflammatory and hepatoprotective properties. Studies have shown that saikosaponin-d can downregulate the expression of the NLRP3 inflammasome and reduce the secretion of IL-1β and IL-18 by inhibiting the activation of the NF-κB pathway and by promoting K48-linked ubiquitination of NLRP3, leading to its proteasomal degradation[104-107]; (2) Ursolic acid: Ursolic acid is widely found in Chinese herbs, such as Crataegus pinnatifida Bunge and Ligustrum lucidum Ait, and exhibits diverse biological activities, including anti-inflammatory, antioxidant, and antitumor effects. In mouse models of UC, ursolic acid inhibited the activation of the NLRP3 inflammasome by directly scavenging ROS, disrupting the TXNIP-NLRP3 interaction, and blocking NLRP3 oligomerization, protecting intestinal barrier function and alleviating intestinal inflammatory injury[108-110]; (3) Emodin: Emodin, an active component of Rheum palmatum L., has anti-inflammatory, hepatoprotective, and intestinal flora-regulatory effects. Studies have found that emodin can inhibit the assembly and activation of the NLRP3 inflammasome by activating the AMPK/mTOR-dependent autophagy pathway, which promotes the autophagic degradation of NLRP3 and ASC, reducing the severity of pancreatic injury and the levels of inflammatory factors in mouse models of AP[111-113]; and (4) Curcumin: Curcumin, the main active component of Curcuma longa, possesses anti-inflammatory and antioxidant properties. In viral hepatitis models, curcumin can reduce the activation of the NLRP3 inflammasome by inhibiting the ROS/NF-κB pathway and by directly binding to the NACHT domain of NLRP3 to block ATPase activity, alleviate liver inflammatory injury, and promote hepatocyte repair[10,11,114-116].

Classic formulas: (1) Buzhong Yiqi decoction: This decoction originated from the Treatise on the Spleen and Stomach (Pi Wei Lun). It functions to tonify the middle energizer, replenish qi, elevate yang, and lift prolapse, and is commonly used for diseases related to spleen-stomach deficiency. Studies have demonstrated that Buzhong Yiqi decoction can inhibit the activation of the NLRP3 inflammasome by by regulating the gut microbiota composition (increasing short-chain fatty acid-producing bacteria and reducing LPS-producing Proteobacteria), enhancing intestinal barrier function via TLR4/NF-κB/MLCK signaling, and improving intestinal inflammatory status in patients with UC[117-119]; (2) Shaoyao decoction: This decoction is a classic formula for treating damp-heat dysentery, with the effects of clearing heat and drying dampness, as well as regulating qi and harmonizing blood. In mouse models of IBD, Shaoyao decoction can reduce the secretion of pro-inflammatory factors and alleviate inflammatory injury of the intestinal mucosa by by upregulating mitogen-activated protein kinase phosphatase 1, which dephosphorylates and inactivates p38 MAPK and JNK, thereby inhibiting the NF-κB/NLRP3 signaling pathway[120-122]; and (3) Qingyi decoction: Qingyi decoction is a commonly used formula for the treatment of AP, possessing the effects of clearing heat and detoxifying toxins, as well as purging fu organs and decreasing turbidity. Research has found that Qingyi decoction can reduce the levels of serum amylase and lipase and alleviate inflammation and necrosis in the pancreatic tissue of mice with AP by inhibiting the activation of the NLRP3 inflammasome[123-125].

In TCM clinical practice, the efficacy of herbal formulas and single compounds is highly dependent on accurate syndrome differentiation. Different TCM syndromes reflect distinct pathological states and require different therapeutic principles. Therefore, beyond summarizing the pharmacological effects on the NLRP3 inflammasome, it is essential to link each intervention to its corresponding TCM syndrome type, core treatment principle, and clinical contraindications. Table 1 provides a syndrome-based overview of the TCM interventions discussed in this review.

Table 1 Traditional Chinese medicine syndrome-based classification, indications, and contraindications of herbal interventions for NOD-like receptor family pyrin domain-containing 3-mediated digestive diseases.

TCM intervention	TCM syndrome type	Core therapeutic principle	Typical digestive indications	Clinical contraindications/cautions
Saikosaponin-d (from Bupleurum Chinense)	Liver depression and spleen deficiency	Soothing liver, harmonizing stomach, tonifying spleen	Chronic hepatitis, MASLD with qi stagnation	Avoid in yin deficiency with fire
Ursolic acid (from Crataegus/Ligustrum)	Damp-heat in the intestines	Clearing heat, resolving dampness, relieving toxicity	UC (active phase)	Caution in spleen deficiency with cold
Emodin (from Rheum palmatum)	Heat toxin and blood stasis	Purging heat, removing stasis, unblocking fu organs	AP, severe constipation	Contraindicated in pregnancy and spleen-stomach deficiency
Curcumin (from Curcuma longa)	Damp-heat jaundice	Clearing damp-heat, promoting gallbladder function, protecting liver	Viral hepatitis, cholestasis	Use with caution in blood deficiency
Buzhong Yiqi decoction	Spleen qi sinking	Tonifying middle-qi, lifting yang, replenishing qi	IBD in remission, chronic diarrhea with fatigue	Contraindicated in Damp-Heat syndrome (e.g., active UC with bloody diarrhea, fever, greasy tongue coating) – may “block the pathogen” and worsen inflammation
Shaoyao decoction	Damp-heat dysentery	Clearing heat, drying dampness, regulating qi and blood	Active UC, bacterial dysentery	Avoid in spleen deficiency with cold diarrhea
Qingyi decoction	Excessive heat in fu organs	Clearing heat, detoxifying, purging fu organs, reducing turbidity	AP (early stage)	Contraindicated in chronic deficiency patterns

AP: Acute pancreatitis; TCM: Traditional Chinese medicine; MASLD: Metabolic dysfunction-associated steatotic liver disease; IBD: Inflammatory bowel disease; UC: Ulcerative colitis.

It is noteworthy that the same formula may be beneficial for one syndrome but harmful for another. For example, Buzhong Yiqi decoction, a qitonifying formula, is indicated for Spleen Qi Sinking syndrome (e.g., chronic fatigue, prolapse, and loose stools). However, in patients with active UC presenting with Damp-Heat syndrome (characterized by bloody diarrhea, tenesmus, fever, and greasy tongue coating), the use of tonifying formulas without simultaneously clearing heat and dampness may block the pathogen, potentially exacerbating intestinal inflammation. Therefore, syndrome differentiation is a prerequisite for the rational application of TCM interventions targeting the NLRP3 inflammasome. Future integrative medicine studies should first classify patients according to TCM syndrome types before evaluating the effects of TCM formulas on inflammasome activity.

Integrated traditional Chinese and Western medicine intervention research

In recent years, integrated TCM and Western Medicine intervention has emerged as a research “hotspot” in the treatment of digestive system diseases. It can exert synergistic effects and improve therapeutic efficacy. For example, in the treatment of MASLD, a therapeutic regimen combining saikosaponin-d with MCC950 can significantly ameliorate hepatic steatosis and inflammatory injury through the dual inhibition of NLRP3 inflammasome activation, with superior efficacy compared with monotherapy[126]. In the treatment of UC, ursolic acid combined with an NF-κB pathway inhibitor can enhance intestinal barrier function and increase the clinical remission rate by synergistically regulating the NF-κB/NLRP3 signaling pathway[127-129]. These findings suggest that integrated TCM-Western medicine intervention has broad application prospects for NLRP3 inflammasome-mediated digestive system diseases and that Western medicine and TCM exhibit distinct characteristics in targeting the NLRP3 inflammasome for digestive disease treatment. Table 2 lists the main intervention agents, their corresponding targets, the diseases which they are applicable to and the important efficacy criteria, offering a convenient reference for the following translational research[1-15,89-91,95-97,104-106,122-124]. A diagram showing the different intervention targets and regulatory pathways of western medicine and TCM on the NLRP3 inflammasome is presented in Figure 2.

Figure 2 Comparison of intervention targets between Western medicine and traditional Chinese medicine on the NOD-like receptor family pyrin domain-containing 3 inflammasome signaling pathway. Visualize the distinct and overlapping targets of Western medicine inhibitors (e.g., MCC950 targeting NOD-like receptor family pyrin domain-containing 3 ATPase activity) and traditional Chinese medicine components (e.g., saikosaponin-d inhibiting nuclear factor kappa B). NLRP3: NOD-like receptor family pyrin domain-containing 3; TLRs: Toll-like receptors; PAMPs: Pathogen-associated molecular patterns; DAMPs: Damage-associated molecular patterns; NF-κB: Nuclear factor kappa B; IL: Interleukin; ROS: Reactive oxygen species; ASC: Apoptosis-associated speck-like protein containing a CARD; GSDMD: Gasdermin D; TCM: Traditional Chinese medicine.

Table 2 Summary of Western medicine and traditional Chinese medicine agents targeting the NOD-like receptor family pyrin domain-containing 3 inflammasome for digestive system diseases.

Category	Name	Target pathway	Disease model	Key efficacy indicators	Ref.
Western medicine inhibitor	MCC950	NLRP3 ATPase/NEK7 interaction	MASLD, AP, UC	Reduced IL-1β, reduced IL-18, ameliorated hepatic steatosis, reduced pancreatic necrosis, improved colitis	Coll et al[89], Perera et al[90], Zheng et al[91]
Western medicine inhibitor	CY-09	NLRP3 ATPase (direct binding)	MASLD, gouty arthritis	Reduced caspase-1, reduced IL-1β, blocked NLRP3 oligomerization	Wang et al[1], Li et al[2]
Western medicine inhibitor	OLT1177	NLRP3 (allosteric inhibition)	MASH, AP	Reduced IL-1β, reduced IL-18, safe in humans (phase II)	Yao et al[3], Xu and Núñez[4]
Western medicine pathway modulator	Pyrrolidine dithiocarbamate	NF-κB	IBD, colitis	Downregulated NLRP3 expression, inhibited cytokine release	Blevins et al[95], Zhai et al[96], Bae and Park[97]
TCM single component	Saikosaponin-d (already present, but enriched mechanism)	NF-κB/NLRP3 ubiquitination	MASLD, liver fibrosis	Reduced NLRP3 inflammasome activation, reduced hepatic inflammation, increased NLRP3 degradation	Islamuddin and Qin[5], Fan et al[104], Lai et al[105], Lim et al[106]
TCM single component	Ursolic acid	ROS scavenging/TXNIP-NLRP3 axis	UC, colitis-associated cancer	Reduced ROS, reduced NLRP3 oligomerization, protected intestinal barrier	Liu et al[6], Swanson et al[7]
TCM single component	Emodin	Autophagy/NLRP3 assembly	AP, colitis	Increased autophagic flux, reduced caspase-1, reduced IL-1β, reduced pancreatic injury	Wang and Ma[8], Zhen and Zhang[9]
TCM single component	Curcumin	ROS/NF-κB/NLRP3	Viral hepatitis, MASLD	Reduced ROS, reduced NF-κB nuclear translocation, reduced NLRP3, reduced IL-1β	Wang et al[10], Man[11]
TCM classic formula	Buzhong Yiqi decoction	Gut microbiota/TLR4/NF-κB	UC, IBD	Improved intestinal barrier, reduced NLRP3, reduced IL-1β, restored tight junctions	Martinon et al[12], Agostini et al[13]
TCM classic formula	Shaoyao decoction	MKP1/NF-κB/NLRP3	DSS-induced colitis	Reduced NLRP3, reduced caspase-1, reduced IL-1β, reduced macrophage infiltration	Mariathasan et al[14], Schroder and Tschopp[15]
TCM classic formula	Qingyi decoction	NLRP3/caspase-1	AP	Reduced serum amylase/lipase, mitigated pancreatic injury	Jiang et al[122], Su et al[123], Fu et al[124]

NLRP3: NOD-like receptor family pyrin domain-containing 3; NF-κB: Nuclear factor kappa B; MKP1: Mitogen-activated protein kinase phosphatase 1; TXNIP: Thioredoxin-interacting proteins; TCM: Traditional Chinese medicine; MASLD: Metabolic dysfunction-associated steatotic liver disease; UC: Ulcerative colitis; AP: Acute pancreatitis; IL: Interleukin; MASH: Metabolic dysfunction-associated steatohepatitis; IBD: Inflammatory bowel disease; ROS: Reactive oxygen species; TLR4: Toll-like receptor 4.

To gain a clearer knowledge of the mechanism by which single TCM treatments affect the NLRP3 inflammasome, we have related each substance to particular molecular stages in the normal activation process (priming, activation, effectuation and negative regulation). Table 3 shows the present information, indicating the different sites of action for each TCM ingredient or preparation.

Table 3 Mapping of traditional Chinese medicine interventions to specific molecular steps of NOD-like receptor family pyrin domain-containing 3 inflammasome activation.

TCM intervention	Priming stage (NF-κB)	Activation stage (ROS/TXNIP/oligomerization)	Effector stage (caspase-1/IL-1β)	Negative regulation (autophagy/ubiquitination)
Saikosaponin-d	Reduced NF-κB translocation	Not directly reported	Reduced caspase-1, reduced IL-1β/IL-18	Increased K48-linked ubiquitination → proteasomal degradation
Ursolic acid	Not directly reported	Reduced ROS → disrupts TXNIP-NLRP3 binding → reduced oligomerization	Reduced caspase-1, reduced IL-1β	NR
Emodin	Not directly reported	Not directly reported	Reduced caspase-1, reduced IL-1β	Increased AMPK/mTOR-dependent autophagy → degradation of NLRP3 and ASC
Curcumin	Reduced NF-κB	Reduced ROS; directly binds NLRP3 NACHT domain → blocks ATPase	Reduced caspase-1, reduced IL-1β/IL-18	NR
Buzhong Yiqi decoction	Reduced TLR4/NF-κB (via microbiota)	Reduced ROS (indirect)	Reduced IL-1β, reduced IL-18	NR
Shaoyao decoction	Increased MKP1 → reduced p38/JNK → reduced NF-κB	Not directly reported	Reduced NLRP3 assembly, reduced caspase-1, reduced IL-1β	NR
Qingyi decoction	Not directly reported	Not directly reported	Reduced NLRP3/caspase-1 axis	NR

NLRP3: NOD-like receptor family pyrin domain-containing 3; ASC: Apoptosis-associated speck-like protein containing a CARD; NF-κB: Nuclear factor kappa B; MKP1: Mitogen-activated protein kinase phosphatase 1; TLR4: Toll-like receptor 4; TXNIP: Thioredoxin-interacting proteins; TCM: Traditional Chinese medicine; NR: Not report; IL: Interleukin; ROS: Reactive oxygen species.

SUMMARY, LIMITATIONS, AND PERSPECTIVES

Summary

As a main protein complex of the innate immunity, the NLRP3 inflammasome serves as an important biochemical center connecting metabolic stress, immune unbalance and the pathogenesis of inflammatory digestive diseases. The abnormal activation of this complex aggravates the intestinal barrier destruction, pancreas tissue necrosis and liver inflammatory fibrosis by means of enhancing the cleavage of caspase-1, inducing the maturation and secretion of IL-1β and IL-18, and promoting pyroptosis. Consequently, it plays a crucial part in the pathophysiological processes of several digestive diseases such as MASLD, IBD and AP. Therefore, the intervention measures for the NLRP3 inflammasome signalling pathway are essential for the accurate treatment of digestive diseases.

Currently, the western medical treatments for the inhibition of NLRP3 inflammasome mainly use specific inhibitors and pathway modulators. These methods have clear targets and definite mechanisms, which can block the assembly of inflammasome or the upstream and downstream signal transduction directly. But they have some limitations such as single-target effects, possible long-term safety risks and difficulties in clinical application. On the other hand, the TCM treatments show distinctive advantages in multi-target and multi-pathway synergistic regulation. The active ingredients of single Chinese herbs (such as saikosaponin-d, ursolic acid and curcumin) and the classical formulas (for example, Buzhong Yiqi decoction, Shaoyao decoction and Qingyi decoction) can precisely regulate the activation of NLRP3 inflammasome via various pathways, such as inhibiting the activation of NF-κB pathway, eliminating ROS, maintaining the balance of intestinal flora and regulating autophagy.

Integrated TCM-Western medicine intervention strategies exert synergistic effects by combining TCM active components with Western medicine-targeted inhibitors, realizing dual regulation of the NLRP3 inflammasome signaling network and significantly improving therapeutic efficacy, thus opening up new avenues for the treatment of digestive system diseases.

Research limitations

Low level of clinical evidence: The majority of supportive studies come from preclinical experiments and lack strong evidence from high-quality, large-scale, randomized controlled clinical trials, particularly for TCM therapies.

Inadequate understanding of the mechanism of TCM effects: Current studies mainly concentrate on confirming ‘whether’ TCM is efficacious, without providing detailed explanation about the specific molecular targets and combined actions responsible for its ‘how’ it works.

Ignoring the specificity of diseases and cells: The activity of NLRP3 is greatly influenced by the environment; but the present research generally applies its role to various diseases or cell types without detailed investigation.

Gap between animal models and real clinical situations: The commonly applied models are unable to adequately reproduce the complexity and progression of human diseases, which might result in suboptimal efficacy or safety during the clinical application.

Insufficiency of FDA-approved NLRP3 inhibitors for digestive diseases: Although a great deal of preclinical studies have been conducted, no NLRP3 inflammasome inhibitor has been licensed for treatment of gastrointestinal, hepatic or pancreatic disorders.

Significant safety and clinical translation failures: Some candidate drugs were discarded in clinical experiments or suspended because of side effects or inefficacy. MCC950 showed hepatotoxicity in prolonged animal tests. Additionally, other inhibitors (like AZD-007) were also stopped prematurely due to their off-target actions. These examples indicate the discrepancy between their expected effectiveness and real clinical outcomes.

Perspectives

First, investigate the specific functions of NLRP3 inflammasome subtypes and their related complexes. In the future, more research is needed to investigate the tissue distribution and cell-specific expression of different NLRP3 inflammasome subtypes, in order to clarify their different mechanisms in various digestive system diseases. Meanwhile, attention should be devoted to the crosstalk between NLRP3 and other inflammasomes (e.g., NLRP1 and NLRC4), as well as the regulatory network involving inflammasomes, intestinal flora, and metabolomics, to provide theoretical support for the development of more targeted intervention targets.

Second, to elucidate the precise molecular mechanisms of TCM interventions targeting the NLRP3 inflammasome, given the multi-component and multi-target characteristics of TCM, technologies such as network pharmacology, molecular docking, and gene editing should be used to identify the direct binding sites between TCM active components of TCM and the NLRP3 inflammasome or its upstream and downstream signaling molecules. The molecular details of TCM-mediated regulation of pathways, including NF-κB, ROS, and autophagy, should be clarified. In addition, further research is needed to explore the synergistic mechanisms of components in TCM formulae, elucidating the scientific connotation of the “monarch, minister, assistant, and guide” compatibility principle in regulating the inflammasome signaling network, and promoting the transformation of TCM intervention mechanism research from “phenomenological description” to “precise molecular mechanism”.

Third, accelerate clinical translation research of integrated TCM-Western medicine intervention strategies; current research remains largely at the cellular and animal experimental stages with relatively insufficient clinical evidence. Large-scale, multi-centre, randomized controlled clinical trials are necessary for confirming the effectiveness and safety of combined TCM and western medicine treatments in the management of digestive system disorders. It is important to carry out comprehensive pharmacokinetic, toxicological and long-term safety evaluations, such as assessing the possible off-target effects, drug-drug interactions and organ-specific toxicities. Standardized manufacturing procedures and quality control systems for TCM extracts should be established, and the optimal doses, treatment periods and compatibility plans for the combined use of TCM and western medicine should be determined to offer standardized advice for the clinical application.

Moreover, we will increase the research on new drugs which aim at inhibiting the NLRP3 inflammasome by combining the merits of TCM and Western medicine. Besides, novel multiple target drug delivery systems (such as nanocarriers including both TCM active ingredients and Western medicine inhibitors) and the newest protein degradation methods will be used as auxiliary measures. Furthermore, artificial intelligence can be utilized to identify TCM substances that possibly have regulatory effects on the NLRP3 inflammasome, reduce the time required for the development of new drugs and offer more effective and safe treatments for digestive system diseases.

In addition to the nanocarrier methods, some new pharmacological techniques such as proteolysis-targeting chimeras (PROTACs) and hydrophobic tagging are also promising for specifically inhibiting the degradation of NLRP3 protein. They can enhance the ubiquitination and proteasomal degradation of NLRP3, thus providing a longer lasting inhibition of the inflammasome compared to the conventional inhibitors. Recently, experimental results have indicated that NLRP3-targeting PROTACs could decrease the level of NLRP3 protein and the secretion of downstream IL-1β in both the cell and animal models of inflammatory diseases[130,131]. These methods have advantages in preventing drug resistance, minimizing side effects and allowing a reduced frequency of administration.F uture research should explore the application of NLRP3-targeted PROTACs and hydrophobic tagging degraders in digestive system diseases such as MASLD, IBD, and AP, and evaluate their safety, efficacy, and potential for combination with TCM components.

CONCLUSION

Integrated TCM-Western medicine intervention strategies targeting the NLRP3 inflammasome have broad application prospects. However, for Western medicine inhibitors, the lack of FDA-approved agents for digestive diseases, together with reported hepatotoxicity and clinical trial failures, underscores the urgent need for safer and more specific compounds. Future research should integrate basic and clinical research resources, deepen mechanistic studies, advance clinical translation and, ultimately, achieve precise and individualized treatment for inflammatory diseases of the digestive system. Future research should integrate basic and clinical research resources, deepen mechanistic studies, advance clinical translation and, ultimately, achieve precise and individualized treatment for inflammatory diseases of the digestive system.