Allergic rhinitis (AR) is one of the most common diseases in otolaryngology, with the incidence rate continuing to rise due to various cultural, economic, and geographical factors. Persistent symptoms such as runny nose, sneezing, nasal congestion, and nasal itching significantly impair patients’ quality of life (Nathan et al., 2008). As a type I hypersensitivity reaction mediated by IgE, AR affects 10%–40% of the global population, placing a significant burden on society and the economy (Zhang et al., 2021a). Recent paradigm shifts emphasize type 2 innate lymphoid cells (ILC2s) as essential innate immune effectors driving AR pathophysiology (Kato, 2019; Luo et al., 2020). Upon allergen exposure, bronchial epithelium-derived alarmins interleukin-33 (IL-33), interleukin-25 (IL-25), and thymic stromal lymphocytin (TSLP) activate ILC2s via ST2 receptors, initiating Th2-polarized immune responses through phosphorylation-dependent activation of NF-κB and MAPK signaling pathways (Hong et al., 2020). The NLRP3 inflammasome, as a standard inflammatory pathway, has been confirmed to play a role in the pathogenesis of AR (Sang et al., 2022). Recent studies have shown that NLRP3 can function as a transcription factor to regulate downstream inflammatory pathways. It can also act as a transcription factor for IL-33 to control the abnormal activation of ILC2s. Furthermore, NLRP3 is involved in the development of AR independently of the NLRP3 inflammasome (Zheng et al., 2021). This review will incorporate the novel idea that NLRP3 acts as a transcriptional regulator in AR through a non-inflammasome pathway. After an initial analysis of the components proven effective against AR, we have discovered that luteolin (Rakariyatham et al., 2018; Hussain et al., 2023; Vajdi et al., 2023), calycosin (Peng et al., 2024), and formononetin (Zhang et al., 2024a; Aladaileh et al., 2019). These three compounds possess strong anti-inflammatory and other pharmacological activities. For example,in a study using an animal model of allergic asthma in mice, calycosin was found to significantly alleviate nasal mucosal inflammation and reduce the levels of Th2-type inflammatory cytokines, such as IL-4, IL-5, and IL-13 (Xue et al., 2021). In addition, luteolin and formononetin also have immunomodulatory effects in various inflammation and immune-related models. Studies have shown that luteolin can reduce the expression of inflammatory factors such as IL-6 and TNF-α by inhibiting the NF-κB and MAPK pathways (Che et al., 2020b). Luteolin has also been shown to alleviate allergic nasal inflammation and inhibit the production of IL-4 in mouse models and peripheral blood mononuclear cells from AR patients (Liang et al., 2020). Formononetin inhibits pro-inflammatory factors and enhances the expression of anti-inflammatory factor IL-10 by regulating the NF-κB and JAK2/STAT3 pathways (Li et al., 2018; Y et al., 2022). Although there is currently a lack of direct evidence of the combined effect of the three monomers in AR models, their independent mechanisms of action support their potential synergistic therapeutic value. Therefore, they can be considered candidate components for treating AR. This review uniquely separates the “nuclear transcriptional function” of NLRP3 from its “cytoplasmic inflammasome function” into two parallel pathways. It systematically compares how three natural compounds intervene selectively at different stages of these pathways, clarifying their complementary mechanisms in treating AR. Due to the side effects associated with hormonal therapy for AR, this review proposes a new therapeutic approach of “non-hormonal, barrier repair first,” encouraging the development of non-hormonal, barrier repair-focused treatments for allergic rhinitis.

In conclusion, this article will examine the potential of the three monomers to influence the NLRP3/IL-33/ILC2s signaling axis, offering a reference for future AR researchers.

NLRP3 is an important pattern recognition receptor. Its structural domain consists of a N-terminal pyrrole domain (PYD), a nucleotide-binding oligomeric domain (NOD), and a C-terminal leucine-rich repeat (LRR) domain that consists of 12 repeats (Sharif et al., 2019). NLRP3 can function as a transcription factor to activate downstream inflammatory pathways. It can also assemble with ASC and caspase-1 to form the NLRP3 inflammasome. Similar to most inflammasomes, the NLRP3 inflammasome consists of the adaptor protein ASC, PYD, and caspase-1. The ASC adaptor protein includes PYD and CARD domains. The PYD domain of ASC binds to the PYD domain of NLRP3, and the CARD domain of ASC binds to the CARD domain of caspase-1, thereby forming the NLRP3 inflammasome (Xu and Núñez, 2023). Activation of the NLRP3 inflammasome results in the release of pro-inflammatory cytokines, including IL-1β and IL-18, thereby promoting inflammation (He et al., 2016).

Research indicates that NLRP3 can act as a transcription factor to activate inflammatory pathways and influence TH2 differentiation. NLRP3 interacts with IRF4 and enhances the ability of IRF4 and IL4 to bind to and activate the promoter. This suggests that NLRP3 may act as a transcription factor for CD4 Th2 cells (Bruchard et al., 2015). In additionally, NLRP3 also has a regulatory effect on IL-33. Recent studies have shown that NLRP3, localized in the nucleus of epithelial cells, interacts with IRF4 and directly binds to the IL-33-specific promoter, thereby activating its transcription and increasing IL-33 expression. The release of IL-33 further activates downstream signaling pathways, triggering inflammatory responses (Zhou et al., 2024; Im and Ammit, 2014). Notably, a study by Hong et al. (Zheng et al., 2021) demonstrated that in the absence of NLRP3, the expression of IL-33 in airway epithelial cells was reduced by 72.3% (p < 0.001), with significant inhibition of ILC2s activation, leading to reduced production of Th2-type cytokines and emphasizing the critical role of this pathway in AR pathogenesis.

AR is a common allergic disease whose development has long been linked to an imbalance between Th1 and Th2 immunity (Zhang et al., 2021a). However, recent studies have shown that the traditional Th1/Th2 imbalance theory only partially explains the complex immunopathological processes underlying AR. With a deeper understanding of the innate immune system, ILC2s have emerged as key effector cells that initiate early responses in AR (Kato, 2019). Additionally, the essential role of epithelial barrier dysfunction in the development of AR has become increasingly evident (Hellings and Steelant, 2020). Epithelial barrier dysfunction is a key factor in the development of AR. A healthy epithelial barrier can effectively prevent allergens from entering the submucosa of the nasal mucosa, while a damaged barrier allows allergens to penetrate, triggering immune responses and leading to AR. As AR becomes chronic, repeated inflammation continues to damage the epithelial barrier, creating a vicious cycle that results in persistent worsening and chronicity of the condition. Additionally, long-term inflammation can cause apoptosis, necrosis, and other forms of programmed cell death in epithelial cells, further weakening the barrier’s integrity and intensifying the inflammatory response AR (Yuan et al., 2025; Huang et al., 2024). According to the conventional mechanism, when the body is exposed to allergens such as mites, pollen, and dust, the epithelial mucosal barrier is disrupted. This breach greatly increases the likelihood of allergen contact with antigen-presenting cells (APCs), such as dendritic cells, thus amplifying local allergic reactions. Naive T cells, upon recognizing specific antigenic peptides in complex with major histocompatibility complex (MHC) molecules presented by APCs, differentiate into Th2 cells (Breiteneder et al., 2019). These Th2 cells secrete a range of cytokines (IL-4, IL-5, IL-13), which further stimulate B cells to produce allergen-specific IgE. The resulting IgE antibodies then bind to high-affinity IgE receptors (FcεRI) on the surfaces of mast cells and basophils (Chen et al., 2025). Upon re-exposure to the same allergen, it binds to IgE, activating mast cells and basophils (El Ansari et al., 2022). This activation triggers degranulation, releasing histamine, leukotrienes, and other inflammatory mediators that cause allergic symptoms (Figure 1). However, as research deepens, increasing evidence shows that the development of AR can occur independently of IgE (Luo et al., 2020; Hong et al., 2020). Dysfunction of the epithelial barrier directly causes the release of inflammatory cytokines (IL-33, IL-25, TSLP). These cytokines can activate innate immune cells, such as mast cells and basophils, in an IgE-independent manner (Hellings and Steelant, 2020; Kortekaas et al., 2020; Nur Husna et al., 2021; Steelant et al., 2016). IL-33 plays a crucial role in initiating type 2 immunity. The response of ILC2s to IL-33 is significantly more severe compared to that of IL-25. Studies comparing IL-33−/− and IL-25−/− gene mice in airway hyperresponsiveness and acetylcholine-induced airway contraction have shown that diseases stimulated by IL-33 are more severe, with clear activation of ILC2s. This indicates that IL-33 is vital in regulating immune-mediated respiratory responses diseases (Barlow et al., 2013). When allergens breach the epithelial barrier, the release of alarmins like IL-33 activates ILC2s by binding to the ST2 receptor (IL-1RL1) on these cells. This triggers downstream NF-κB and MAPK signaling pathways, leading to high expression of GATA3 and promoting the secretion of Th2-type cytokines ILC2s (Dwyer et al., 2022). Importantly, IL-33 works together with IL-25 and TSLP to boost the response: TSLP increases IL-33 sensitivity by raising ST2 receptor levels on ILC2s, while IL-25 extends ILC2s survival through activation of the STAT5 pathway, creating a positive feedback loop. Activated ILC2s not only release IL-5 and IL-13 directly but also promote Th2 cell polarization via MHC II antigen presentation, enabling communication between adaptive and innate immunity (Hong et al., 2020; Kitano et al., 2022) (Figure 2).

In summary, blocking the activation of ILC2s and their release of Th2-type cytokines is a key strategy for treating AR. Although traditional Chinese medicine (TCM) formulas have proved effective for AR, their complex makeup makes it hard to pinpoint the specific components responsible for their healing effects. This review will, therefore, select effective monomers from TCM formulas used to treat AR based on formula analysis and previous research, to clarify their therapeutic mechanisms.

Recent studies have shown that respiratory symptoms such as bronchial asthma, chronic pharyngitis, and allergic rhinitis, which cause coughing, expectoration, and wheezing, are linked to local inflammation infiltration (Eifan and Durham, 2016; Poletti et al., 2006). The main treatment approach for these conditions involves eliminating chronic airway inflammation. Corticosteroids are commonly used in Western medicine to reduce airway inflammation, but their numerous side effects limit their long-term use. According to the literature, 38.3% of patients with allergic rhinitis are refractory to corticosteroids treatment (Sun et al., 2023). In addition, long-term use of corticosteroids may cause weight gain or glaucoma patients (Santiago and da, 2014). Currently, medications are being developed to target type 2 immune responses in AR. Only a few biological agents targeting cytokines such as IL-33 are under development, with most still in phase I or II clinical trials (Hong et al., 2020). Therefore, given the serious treatment situation for AR, it is urgent to find a component with higher safety and fewer side effects to replace it corticosteroids.

Based on statistical analysis, we found that among the TCM with fewer side effects in treating AR, monomeric components such as luteolin, calycosin, and formononetin are particularly significant. The statistical results are as follows (Table 1; Table 2).

After conducting a statistical analysis of the effectiveness of TCM components in treating AR, we identified the usage frequencies of three monomers—luteolin, calycosin, and formononetin—in AR research. It is important to note that the analysis of the prescription serves only as a preliminary indication, and final confirmation of the active ingredients still requires further experimental validation. To better understand the therapeutic potential of these TCM monomers, we performed a detailed comparison with conventional drugs (Table 3). The results showed that these TCM monomers have notable advantages in reducing inflammation, repairing nasal mucosal barriers, and lowering recurrence rates, while also exhibiting lower toxicity and fewer side effects. This comparative analysis enhances our overall understanding of the potential of TCM monomers in AR treatment and provides valuable references for future research and clinical application.

Luteolin exerts strong anti-inflammatory effects by blocking the activation of the NLRP3/IL-33/ILC2s signaling pathway through multiple mechanisms, thereby decreasing the release of inflammatory substances cytokines (Che et al., 2020a; Che et al., 2020b). Its potential therapeutic value in AR has been preliminarily confirmed. Studies have demonstrated that luteolin exerts anti-inflammatory effects by inhibiting the PI3K-Akt signaling pathway (Gao et al., 2023; Chai et al., 2024). However, this pathway is vital for cell growth, proliferation, and survival, and excessive inhibition may cause cell apoptosis and other negative effects. The PI3K-Akt signaling pathway is closely linked to various diseases and is essential for maintaining normal cellular functions. When luteolin inhibits this pathway, it can disrupt the existing signaling balance within cells, leading to halted cell growth and increased apoptosis. Further clinical trials are needed to assess the safety and effectiveness of luteolin. Calycosin, which influences the activation of NLRP3 and its downstream signaling pathways (Zhang et al., 2022b; Chen et al., 2021), suppresses the secretion of related inflammatory cytokines and maintains the integrity of the epithelial barrier (Jia et al., 2018; Yuan et al., 2020), demonstrating significant anti-inflammatory and immunomodulatory effects. Formononetin, like calycosin, promotes the repair of the epithelial barrier (Yuan et al., 2020) and reduces the production of upstream cytokines in AR, thereby alleviating downstream inflammatory responses (Figure 2). The bioavailability of calycosin and formononetin in vivo has been shown to be low through chemical analysis and other methods (Lu et al., 2025; Guo et al., 2023; Xiang et al., 2025), which greatly limits their potential for use in treating AR. The absorption efficiency of drugs in the gastrointestinal tract and the strength of the first-pass effect can both cause low effective concentrations in the body, thereby restricting therapeutic effectiveness. To tackle this problem, future research could use nanocarrier delivery (Zou et al., 2024) to enhance the solubility and stability of the drugs, protect them from the harsh gastrointestinal environment, and promote their efficient release at target tissues, thereby improving overall bioavailability and achieving better therapeutic outcomes. After an in-depth investigation into the therapeutic effects of the three monomers on AR, it has been found that these three monomeric compounds exhibit multidimensional synergistic effects in AR treatment: luteolin focuses on inhibiting the signaling pathway (Liang et al., 2020), calycosin enhances barrier function (Jia et al., 2018; Yuan et al., 2020), and formononetin has the advantage of epigenetic regulation. Notably, all three compounds can downregulate IL-33 through different mechanisms (Li et al., 2018; Che et al., 2020b; Elsherbiny et al., 2020). However, their specific sites of action differ, indicating that combination therapy may produce additive effects. Future studies should explore whether the combined use of these compounds can improve therapeutic outcomes. To better illustrate the individual effects of these three monomers in AR treatment, the following table (Table 4) provides a detailed overview of their core structures, binding energies with NLRP3, inhibitory rates on IL-33, and barrier repair efficiencies As illustrated in Table 4, luteolin has the highest binding energy (a measure of interaction strength) with NLRP3 (−8.2 kcal mol⁻¹), This pronounced interaction physically occludes the ASC-binding on NLRP3, thereby aborting inflammasome assembly (Lee et al., 2021). This is consistent with its strong inhibitory effect on IL-33 expression (inhibition by 68%). Calycosin, although displaying an intermediate binding energy (−7.5 kcal mol⁻¹), demonstrates superior efficacy in restoring epithelial barrier integrity, intercepting the ‘inflammasome–barrier damage–alarmin release’ feed-forward loop at an intermediate step, consequently diminishing IL-33 secretion and indirectly restraining ILC2 activation. Formononetin, possessing the lowest NLRP3-binding energy among the three compounds (−6.9 kcal mol⁻¹), appears to operate via an allosteric mode—interfering with AP-1/NF-κB-mediated transcriptional elongation of IL-33 rather than direct NLRP3 engagement—thus exemplifying a ‘weak binding–strong transcriptional repression’ paradigm.

The three monomers have complementary characteristics: ‘luteolin targeting intracellular signaling, calycosin strengthening barrier function, and formononetin offering a balanced approach’. These data not only provide experimental evidence for the synergistic effects of the three monomers but also establish a foundation for future research on the potential benefits of their combined use. By examining these specific indicators, we can better understand the unique strengths of each monomer and their potential value in AR treatment.

The NLRP3/IL-33/ILC2s signaling pathway plays a crucial role in the pathogenesis of AR by activating ILC2s via NLRP3 and cytokines secreted by damaged epithelial cells, thereby promoting the secretion of Th2-type cytokines and exacerbating inflammatory responses. The identification of the NLRP3/IL-33/ILC2s signaling axis provides a novel target for AR treatment. Luteolin, calycosin, and formononetin exert synergistic effects through multi-target and multi-level mechanisms, effectively interrupting the pathological cycle of ‘epithelial damage-alarmin release-ILC2s activation-Th2 polarization’. Compared with traditional corticosteroid therapy, this multi-target regulatory regimen based on natural plant monomers shows significant safety advantages. In light of the limitations of the aforementioned monomers, future research will focus on the development of nanoparticles and nasal spray formulations (Shrestha et al., 2020) to achieve more precise and convenient drug delivery. Meanwhile, on the basis of establishing the synergistic effects of the three monomers, a determination of the synergistic index of the three components will be carried out, and the synergistic effect of combined medication will be verified by the Chou-Talalay method. This will further optimize their ratios and dosing regimens, enabling the drug combination to exert remarkable therapeutic effects at lower doses, thereby enhancing the safety and efficacy of drug therapy as a whole and bringing breakthrough progress to the field of AR treatment.