Allergic diseases (ADs) represent one of the most common diseases prevalent in numerous parts of the world (Weiss and Sullivan, 2001; Comeau and Ziegler, 2010; Wu et al., 2021). Increasing prevalence of these diseases is seen as a worldwide concern leading to significant rise in healthcare spending. According to the World Health Organization (WHO), ADs are the fourth leading chronic disease, with 20 to 30% of the people worldwide currently affected, which will steadily rise to 50% by 2050 (Papadopoulos et al., 2012; Wu et al., 2021). The quality of life of the affected individuals is severely reduced by chronic eczematous lesions, pruritus, sleep loss, food limitations, and psychosocial affections, even if it is a serious condition with a milder severe form. Furthermore, ADs are also related to the development and malignant progression of many cancers (El-Zein et al., 2014), inflammatory (Barnes 2000), asthma (Eguiluz-Gracia et al., 2018), rheumatologic (Murdaca et al., 2019), neurological diseases (Tzeng et al., 2018), and cardiovascular disorders (Silverberg et al., 2018).

Thymic stromal lymphopoietin (TSLP) belongs to the interleukin 2 (IL-2) family and is central in developing atopic diseases such as atopic dermatitis, allergic rhinitis, and asthma. TSLP works via a heterodimeric receptor complex composed of the thymic stromal lymphopoietin receptor CRLF2 and the IL-7Rα chain. Upon binding, STAT5 is phosphorylated, leading to the expression of downstream transcription factors. TSLP-activated dendritic cell (DCs) cause vigorous multiplication of the allogeneic CD4⁺ T cells, which later differentiate into T helper 2 (Th2) cells and release allergy-promoting cytokines, such as IL-4, IL-5, IL-13, and TNF-, activating B and mast cells as well as other leukocytes. In the presence of IL-4 and TSLP, naive CD4⁺ T cells differentiate into IL-4⁺ and IL-4- Th2 cells. Following such an occurrence, the IL-4-negative population evolves to form a distinct subgroup of IL-13⁺, IL-5⁺, and IL-9⁺ T cells. High TSLP levels in lymph nodes induced the formation of a population of IL-4- and IL-13⁺ T cells in vivo. Many studies have emphasized that aberrant TSLP signaling is closely associated with allergic inflammation, including asthma, allergic rhino conjunctivitis, atopic dermatitis, anaphylaxis, and urticaria (Akdis, 2012). Indeed, growing bodies of experimental and clinical evidence suggest that high TSLP expression is associated with allergic diseases in humans and mice.

Moreover, another study has shown that inhibiting the TSLP receptor in a primate animal model can lead to decreased allergic inflammation (Cheng et al., 2013). However, despite the urgency to investigate anti-allergic medications, there have been relatively few studies on naturally existing substances that specifically modulate the TSLP signaling pathways. Thus, inhibiting the display and secretion for targeting TSLP, IL-25, and IL-33 by phytochemicals is a feasible preventive or therapeutic approach that may assist in treating allergic inflammation, atopic dermatitis, asthma, and other allergic states.

Natural compounds have remained instrumental in drug discovery, encompassing various applications such as anti-allergic, anti-inflammatory, antioxidant, antibiotic, anti-bacterial, and even anti-cancer properties (Newman, 2021). Approximately 60% of newly approved small molecule drugs by the Food and Drug Administration (FDA) in the last three decades are believed to have originated from or are connected to natural products (Patridge et al., 2016). Significantly, several methodologies have been used to investigate their pharmacological effects, leading to notable advancements in the field of pharmaceutical research (Atanasov et al., 2021; Wainwright et al., 2022). Multiple allergy medications, such as antihistamines, corticosteroids, anti-inflammatory medications, and mast cell blockers, effectively alleviate symptoms. However, these treatments have side effects and certain limitations when used for prolonged durations (Bantz et al., 2014). Although traditional herbal medicines and their phytochemicals have long been used to treat ADs, little is known about the potential of inhibiting the TSLP pathway using natural compounds for treating the disease (Adhikary et al., 2021). In our continuing efforts to study the potential anti-allergic effects of naturally occurring compounds (Park et al., 2017; Nguyen et al., 2018; Park et al., 2019b; Vinh et al., 2019a, 2019b; Nguyen et al., 2020; Shin et al., 2021), the current review is the first comprehensive report on the possible natural compounds inhibiting the TSLP pathway. Furthermore, it offers a scientific basis for further investigating the mechanisms underlying anti-allergic properties and their potential application in related diseases.

For ages, herbal therapy has been used to heal and treat various illnesses. Their wide availability, affordability, and lack of side effects compared to synthetic pharmaceuticals have led to the worldwide wise utility of such herbal medicines. The WHO estimates that around 60% of people worldwide and about 80% of those living in underdeveloped nations rely on herbal medicines for their primary healthcare needs (Newman, 2021). TSLP, a cytokine that participates in the immune responses, crucially regulates allergic conditions and asthma (Comeau and Ziegler, 2010). It is primarily produced by epithelial cells, such as those lining the respiratory and gastrointestinal tracts. It acts as an early warning signal in response to environmental triggers, such as allergens. The mechanism of action of TSLP in allergy involves activating various immune cells that promote allergic inflammation. Upon exposure to allergens such as pollen, dust mites, or certain dietary proteins, epithelial cells in the airways or gut secrete TSLP, which subsequently engages with dendritic cells and antigen-presenting cells, playing a vital role in the initiation and control of immunological responses (Adhikary et al., 2021). TSLP activates DCs by binding to specific receptors on their surface, leading to their maturation and migration to nearby lymph nodes. In the lymph nodes, the DCs present the allergenic proteins to the naive T cells, initiating an allergic immune response. Upon interaction with TSLP-activated DCs naive T cells differentiate into Th2 cells, a specific subset of T helper cells that release cytokines such as IL-4, IL-5, and IL-13 (Fig. 1) (Shen et al., 2012). These cytokines promote the recruitment and activation of other immune cells, such as eosinophils, mast cells, and basophils, involved in allergic inflammation. Eosinophils release inflammatory mediators and promote tissue damage. Mast cells and basophils release histamine, leukotrienes, and other chemicals that cause the symptoms associated with allergic reactions, including itching, swelling, mucus production, and bronchoconstriction. Additionally, TSLP can directly act on other cell types, such as B cells, which produce antibodies, and epithelial cells, further amplifying the allergic response (Yoou et al., 2016a). Thus, TSLP secretion by epithelial cells in response to allergens leads to the activation of DCs, differentiation of Th2 cells, and subsequent release of inflammatory cytokines, contributing to the allergic immune response and the development of allergic inflammation in tissues such as the airways or gut. Gaining insight into the processes of TSLP and its significance in allergic illnesses is crucial for the development of novel therapeutic strategies to address allergies and asthma. Researchers are exploring the potential of targeting TSLP or its receptors to modulate allergic responses and alleviate symptoms associated with allergic diseases. The ability of the medicinal extracts to treat AD has been delineated in this review.

Figure 1. The diagram illustrates the mechanism of action of phytochemicals in allergic disorders. NRF2: Nuclear factor erythroid-2-related factor 2, ROS: Reactive oxygen species, NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells, TSLP: Thymic stromal lymphopoietin, TLR2: Toll-like receptor 2, Th2: T helper 2 cell.

Alpinia intermedia (AI)

The perennial plant Alpinia intermedia (AI), traditionally used as folk medicine in Japan, ameliorated the severity of AD both in vitro and in vivo. In vitro study, AI extract inhibited TSLP expression and mast cell degranulation. In vivo, topical application of AI extract to the mice skin significantly reduced scratching behavior and improved skin barrier function. The addition of the extracts to cell cultures resulted in a reduction of TSLP mRNA expression in PAM212 keratinocytes, decreased degranulation in bone marrow-derived cultured mast cells and neurite outgrowth in PC12 cells. Thus, it indicates that the extract of this plant enhances skin condition by suppressing various inflammatory responses, which may serve as a therapeutic intervention for patients with atopic dermatitis (Amagai et al., 2017).

Artemisia scoparia (AS)

Artemisia scoparia (AS) has been historically used in treating inflammation. It exerts anti-inflammatory effects by reduction of TSLP and interleukin production via suppressing caspase-1 activity in vitro. AS also inhibited MAPK and NF-κB signaling pathway to reduce cytokine production (Nam et al., 2018). In an in vivo study, AS significantly reduced the expression of histamine and cytokines, alleviated clinical symptoms of DNFB-induced skin lesions and associated scratching behaviors, diminished the infiltration of inflammatory cells in skin lesions, and lowered inflammatory cytokines within these lesions (Ryu et al., 2018).

Brassica oleracea (BO)

Brassica oleracea (BO) refers to diverse crop plants from the Brassicaceae family, such as cabbage or broccoli. The water extract of Brassica oleracea significantly reduced the secretion of TSLP and caspase-1 activity in vitro by using phorbol 12-myristate 13-acetate and A23187 (PMACI)-stimulated human mast cells (HMC-1 cells). BO also substantially inhibited the levels of inflammatory cytokines, which is strongly regulated by its main bioactive compound sulforaphane (Jeon et al., 2020).

Combretum quadrangulare (CQ)

Combretum quadrangulare (CQ), a small tree of the family Combretaceae distributed in southeastern Asia. The ethanol extract of CQ substantially suppressed the mRNA expression of cytokines in BALB/c mice with DNCB-induced atopic dermatitis-like skin lesions by suppressing MAPK signaling. CQ also reduced serum IgE levels and inhibited mast cell infiltration. Moreover, it significantly increased the expression of filaggrin, so restoring epidermal thickness and easing the clinical symptoms of AD (Park et al., 2020).

Fructus cnidii (FC)

Fructus cnidii (FC), a traditional Chinese medicine called ‘she-chuang-zi’, have reported to show anti-allergic activity. Ethyl acetate fraction of FC was found to successfully alleviate symptoms similar to AD in in vivo research. In addition to suppressing the quantity of cytokines and serum immunoglobulins, it prevented mast cells from diffusing into the bloodstream. Furthermore, scratching behavior and skin thickness were also alleviated. So, FC might be potent treatment for AD and other inflammatory disease (Chen et al., 2020a).

Gardenia jasminoide (GJ)

Gardenia jasminoides (GJ), an evergreen flowering plant called gardenia or cape jasmine, alleviated AD-like skin lesions, ear swelling and scratching behavior by its topical application onto mice. The GJ extract not only decreased the levels of serum IgE and other cytokines, but it also prevented the invasion of inflammatory cells when it was administered. And it increased skin barrier protein expression in mice. Additionally, its major components geniposidic acid and gardenoside have been reported to inhibit the production of chemokines in HaCaT cells (Park et al., 2019d).

Morinda citrifolia (MO)

Morinda citrifolia (MO), commonly referred to as Noni, demonstrated the ability to suppress histamine release and various chemokine levels associated with AD in vitro. In an in vivo experiment, MO reduced Th2-mediated cytokine levels in mouse skin lesions and restored the expression of skin barrier proteins, including filaggrin, loricin, and occludin. MO reduced epidermal ear thickness, mast cell infiltration, and cytokine levels in vivo (Kim et al., 2020).

Panax ginseng (PG)

Panax ginseng (PG), world’s most well-known processed ginseng product, showed therapeutic effect in atopic dermatitis. PG extract suppressed the expression of well-known chemoattracts for Th2 cells, MDC (CCL22, Macrophage-derived chemokines) and TARC (CCL17, Thymus and activation-regulated chemokines), by inhibition of MAPK signaling pathway in vitro (Park et al., 2019c). PG extract reduced itching sensation by suppressing Th2-driven inflammation and reduced cytokine levels like IgE, IL-31, TNF-α and TSLP in vivo. Its treatment also recovered ear size and skin moisture. A 2,4,6-trinitro-1-chrolobenzene (TNCB) treated on the ears and backs of NC/Nga mice was used in the study (Lee and Cho, 2017).

Polygonum tinctorium (PT)

Polygonum tinctorium (PT), famous for traditional indigo dye, have shown anti-inflammatory activities. By blocking the caspase-1 signalling pathway, PT reduced inflammatory cytokine expression in AD-like conditions in vitro and in vivo. In an animal model of allergic rhinitis, the research shows that PT influences the synthesis of many cytokines, including TSLP, IL-32 and many others (Jeong et al., 2014). One study demonstrated that oral administration of PT diminished the severity of AD-like lesions in DNFB-induced skin, subsequently leading to reductions in inflammatory mRNA and protein levels, serum IgE, interleukin-4, and caspase-1 expression in mast cells. Topical treatment enhanced clinical symptoms in DNFB-induced AD mice by reducing histamine and IgE levels and inhibiting the synthesis and mRNA expression of TSLP (Han et al., 2014a).

Sargassum horneri (SH)

Sargassum horneri (SH) is a widely recognized and edible seaweed renowned for its antioxidant properties. SH extracts exhibited anti-inflammatory effects both in vitro and in vivo. In TNF-α/IFN-γ-stimulated HaCaT keratinocytes, SH extracts reduced the levels of various cytokines and chemokines (Han et al., 2021b). One of the studies examines the anti-inflammatory efficacy of SH in alleviating asthma symptoms aggravated by Particulate Matter in asthmatic mice. SH mitigates PM-induced granulocyte infiltration, inhibits TLR2/4/7 expression, and diminishes MyD88-dependent NF-κB activation. This leads to reduced expression of pro-inflammatory cytokines and chemokines, indicating SH as a viable choice for PM-exacerbated severe asthma (Herath et al., 2020).

Solanum tuberosum (ST)

Solanum tuberosum (ST), an herbaceous perennial grown for edible tubers, is a potential treatment for AD. Its ethanol extract has been reported to lower systemic Th2 response, which is induced by Th2 cell cytokines, via inhibition of TSLP production and blocking nuclear translocation of NF-κB p65. Additionally, it restored the protein production of filaggrin in skin lesions analogous to AD in vivo using NC/Nga Mice (Yang et al., 2015).

Combination of natural products

Cinnamomum cassia and Artemisa annua (CIAR): The combination of two herbal medicines, Cinnamomum cassia and Artemisa annua extracts (CIAR), effectively reduced the Th2-type cytokine response by suppression of TSLP expression which leads to Th2-type cytokine activation, in in vivo experiment, using OVA-Induced Balb/C Mice. In addition, CIAR was able to decrease the number of inflammatory cells in the blood as well as the infiltration of immune cells. It markedly decreased the thickness of the respiratory epithelium, therefore relieving asthma-like symptoms (Bae et al., 2022).

Huang-Lian-Jie-Du Decoction (HLJDD): Huang-Lian-Jie-Du Decoction (HLJDD) is a renowned traditional Chinese herbal formula with historical origins dating back to the Tang dynasty. It consists of various plant components in each particular proportions. HLJDD lowered the production of cytokines and inflammatory cell infiltration. It also significantly improving the clinical AD-like symptoms in mice (which were induced by 2,4-dinitrobenzene) with skin lesions by inhibition of NF-κB and MAPK pathways and increasing filaggrin expression (Chen et al., 2020b).

Madi-Ryuk (MDR): Madi-Ryuk (MDR) comprises various medicinal herbs, including Pinus densiflora, Carthamus tinctorius, Hordeum vulgare, Ulmus davidiana, Taraxacum coreanum, Leonurus japonicas, Angelica gigas, Achyranthes aspera, and Glycyrrhiza uralensis (Kim et al., 2019b). MDR decreased the inflammatory cytokine levels and NO production in vitro using human mast cell HMC-1. It also suppressed the release of histamines and TSLP production by inhibition of NF-κB, and MAPK signaling pathways. Furthermore, MDR reduced inflammatory cell infiltration via downregulation of caspase 1 expression in vivo (Kim et al., 2018).

Yu-Ping-Feng-San (YPFS): Yu-Ping-Feng-San (YPFS), a Chinese herbal decoction also known as Jade-Screen Powder, consists of Radix Astragali, Rhizoma Atractylodis Macrocephalae, and Radix Saposhnikovia (Bao et al., 2020). Clinically, YPFS is widely used to treat allergic disorders with few adverse reactions. It inhibited overproduction of TSLP and IL-4, 5, 13 both in vivo and ex vivo. Furthermore, YPFS effectively alleviated AD-like symptoms by upregulation of cell junction proteins including level of desmoglein-1 (DSG1), claudin-1 (CLDN-1) and occludin (OCC) (Zheng et al., 2019).

Natural product ointment

Jawoongo: Jawoongo, a traditional herbal medicine containing Lithospermum root and Angelica gigas, exhibits anti-inflammatory properties in vitro and in vivo. In in vitro study, it inhibited NO production and suppressed the expression of inflammation-associated molecules. In in vivo study, its ointment form reduced skin thickness and mast cell infiltration into mouse skin lesions. Furthermore, the administration of Jawoongo has the ability to suppress the expression of cytokines and the activation of the NF-kB and MAPK pathways in a variety of immune cell types. As a whole, it indicates that Jawoongo has the potential to be an effective candidate medicine for the treatment of AD (Ku et al., 2018).

Qingpeng (QP): Qingpeng ointment (QP), a chinese medicine used in treatment of AD, has been known for treating chronic itch. It suppressed scratching behavior by inhibition of MAPK signaling pathway in vivo (squaric acid dibutylester (SADBE) in mice). It also downregulated itch-related genes including TRPV4 and TSLP in the epidermis. Additionally, QP therapy decreased Th1/2 cytokine productions, so it might be a good clinical candidate for treatment of AD-like symptoms (Gong et al., 2019). Table 1 showed a summary of medicinal plants targeting TSLP pathways for allergic disease.

Table 1 Medicinal plants targeting TSLP pathways for allergic disease treatment: a summary

	Extract	Results	In vitro/In vivo	References
1	Alpinia intermedia	Suppression of cytokine expression and inflammatory cell infiltration. Alleviation of clinical AD-like symptoms.	In vitro & in vivo	Amagai et al., 2017
2	Artemisia scoparia	Suppression of cytokine production by blocking caspse-1 signaling pathway. Alleviation of clinical AD-like symptoms.	In vitro & in vivo	Nam et al., 2018; Ryu et al., 2018
3	Brassica oleracea	Decrease TSLP production by blocking caspase-1 signaling pathway.	In vitro	Jeon et al., 2020
4	Combretum quadrangulare	Suppression of cytokine expression by inhibition of MAPK signaling pathway. Alleviation of epidermal thickness via skin barrier function regulation.	In vitro & in vivo	Park et al., 2020
5	Fructus cnidii	Inhibition of Mast cell infiltration. Alleviation of clinical AD-like symptoms.	In vivo	Chen et al., 2020a
6	Gardeia jasminoides	Decrease serum IgE level and inflammatory cell infiltration. Increase skin barrier protein expression and amelioration of clinical AD-like symptoms.	In vivo	Park et al., 2019d
7	Morinda citrifolia	Suppression of TSLP expression. Increase skin barrier protein expression and amelioration of clinical AD-like symptoms.	In vitro	Oh et al., 2021b
8	Panax ginseng	Suppression of cytokine expression by inhibition of MAPK signaling pathway. Alleviation of clinical AD-like symptoms.	In vitro & in vivo	Lee and Cho 2017; Park et al., 2019c
9	Polygonum tinctorium	Decrease cytokine expression by blocking caspase-1 signaling pathway.	In vitro & in vivo	Han et al., 2014a; Jeong et al., 2014
10	Sargassum horneri	Reduce cytokine expression and inflammatory response by inhibition of NF-κB pathway.	In vivo	Herath et al., 2020
11	Solanum tuberosum	Suppression of TSLP production by inhibition of NF-κB pathway.	In vitro	Yang et al., 2015
12	CIAR	Suppression of TSLP expression and mast cell infiltration.	In vitro & in vivo	Bae et al., 2022
13	Huang-Lian-Jie-Du	Improve clinical AD-like symptoms by inhibition of MAPK and NF-κB signaling pathway.	In vivo	Chen et al., 2020b
14	Madi-Ryuk	Inhibition of inflammatory response by blocking caspase-1, MAPK and NF-κB signaling pathway.	In vitro & in vivo	Kim et al., 2018; Kim et al., 2019b
15	Yu-Ping-Feng-San	Suppression of cytokine production. Alleviation of clinical AD-like symptoms by upregulation of cell junction proteins.	In vitro & in vivo	Zheng et al., 2019; Bao et al., 2020
16	Jawoongo	Suppression of inflammatory response and recovery of epidermal skin thickness.	In vitro & in vivo	Ku et al., 2018
17	Qingpeng ointment	Suppression of chronic itch by regulation of itch-related genes and MAPK signaling pathway.	In vitro & in vivo	Gong et al., 2019

IgE: Immunoglobulin E, MAPK: Mitogen-activated protein kinase.

Secondary metabolites from medicinal plants, including alkaloids, terpenoids, phenolics, and saponins, have various pharmacological effects. In this review, we describe how natural phytochemical components inhibit TSLP in the context of allergy by targeting the TSLP pathways. The detailed references and natural agents that inhibit TSLP are listed in Table 2.

Table 2 Phytochemicals as Therapies for Allergic Diseases Targeting TSLP Pathways

	Compound	Result	Source	In vitro orin vivo	References
	Alkaloids
1	Berberine	Inhibition of TSLP production via caspase-1/NF-κB signaling pathway.	Berberis vulgaris	In vitro	Kim et al., 2015a
2	Neferine	Suppression of cytokine expression via inhibition of NF-κB signaling pathway.Amelioration of AD-like clinical symptoms.	Nelumbo nucifera	In vitro	Yang et al., 2021
3	Tryptanthrin	Anti-proliferative effect on TSLP-stimulated mast cell proliferation via MDM2/p53 pathway regulation.	Strobilanthes cusia	In vitro	Han et al., 2016
	Flavonoids
4	Acteoside	Suppression of mast cell proliferation through regulation of MDM2/STAT pathway and apoptotic markers	Verbascum sinuatum L	In vitro	Yoou et al., 2015
5	Baicalein	Inhibition of TSLP production via blocking TSLP and TSLP receptor (TSLPR) interactionSuppression of type 2 immune response via STAT5 signaling pathway.	Scutellaria baicalensis	In vitro & in vivo	Park et al., 2019a; Yoshida et al., 2021; Zhu et al., 2021
6	Epigallocatechin-3-O-gallate	Inhibition of TSLP production via caspase-1/NF-κB signaling pathway.	Camellia sinensis	In vitro	Moon et al., 2012a
7	Eupatilin	Inhibition of inflammatory cytokine expression and recovery of skin barrier proteins.	Artemisia asiatica	In vivo	Jung et al., 2018
8	Fisetin	Attenuation of LPS induced inflammation and AD-like clinical symptoms.	Rhus cotinus	In vivo	Kim et al., 2014
9	Formononetin	Inhibition of DC activation and T cell differentiation.Suppression of TSLP/IL-33 expression via GPER signaling pathway.	Trifolium pratense	In vitro & in vivo	Shen et al., 2014; Zheng et al., 2019; Yuan et al., 2020; Yoshida et al., 2021; Yuan et al., 2021
10	Kaempferol	Inhibition of TSLP production via MAPK and NF-κB signaling pathway.	Ginkgo biloba	In vitro	Nam et al., 2017
11	Naringenin	Inhibition of TSLP production via NF-κB signaling pathway and suppression of mast cell proliferation through regulation of MDM2/STAT pathway.	Citrus reticulata	In vitro & in vivo	Moon et al., 2011; Han et al., 2018
12	Quercetin	Inhibition of cytokine production by MAPK and NF-κB signaling pathwayInhibition of mast cell deregulation and infiltration by PLC-γ signaling pathway.	Camellia sinensis	In vitro & in vivo	Jung et al., 2010; Gupta et al., 2016; Sozmen et al., 2016b; Beken et al., 2020
13	Saponarin	Inhibition of inflammatory cytokine expression via MAPK signaling pathway and maintaining skin moisture.	Hordeum vulgare L	In vivo	Min et al., 2021
14	Calycosin	Recovery of epithelial tight junction by inhibition of HIF1-α.Inhibition of TSLP/IL-33 production via TLR4 mediated NF- κB signaling pathway.	Astragalus propinquus	In vitro & in vivo	Shen et al., 2014; Tao et al., 2017; Jia et al., 2018; Yuan et al., 2020
15	Catechin	Attenuation of nasal allergic reaction via modulation of T helper cell differentiation.Inhibition of inflammatory cytokine production by blocking NF-kβ signaling pathway.	Camellia sinensis	In vitro & in vivo	Pan et al., 2018a
16	Chrysin	Inhibition of inflammatory cytokine expression via MAPK and NF-kβ/EGR-1 signaling pathway	Passiflora caerulea	In vitro & in vivo	Yeo et al., 2021a
17	Chrysophanol	Suppression of cytokine expression via caspase-1/NF-kβ and MAPK signaling pathway.Inhibition of mast cell proliferation by regulation of MDM2/p53 and apoptosis axis.	Rheum rhabarbarum	In vitro & in vivo	Jeong et al., 2018a; Han et al., 2019; Kim et al., 2019a
18	Cimifugin	Suppression of cytokine expression and recovery of tight junction deficiency.	Saposhnikovia divaricata	In vitro & in vivo	Wang et al., 2017
19	Curcumin	Decrease of TSLP production via caspase-1/NF-kβ and STAT6/GATA3 signaling pathway.	Curcuma longa	In vitro & in vivo	Moon et al., 2013
20	Eckol	Suppression of chemokine and cytokine production via NF-kβ and MAPK signaling pathway.	Ecklonia cava	In vitro	Cho et al., 2020
21	Ferulic acid	Decrease of chemokine production and suppression of immune cell infiltration.	Ferula communis	In vitro & in vivo	Brugiolo et al., 2017a
22	Licochalcone A	Suppression of TSLP and cytokine production by decrease the DNA-binding activity of NF-kβ.	Glycyrrhiza glabra	In vitro	Kim et al., 2015c
23	Manoalide	Suppression of cytokine expression via blocking NF-kβ and MAPK signaling pathway	Luffariella variabilis	In vitro	Yeom et al., 2021
24	Resveratrol	Suppression of IL-25, IL-33, TSLP expression and recovery of epidermis irregularity.	Veratrum grandiflorum	In vivo	Sozmen et al., 2016a
25	Rosmarinic acid	Inhibition of TSLP-induced mast cell proliferation by regulation of MDM2/pSTAT6.Blocking TSLP signaling pathway.	Rosmarinus officinalis L.	In vitro & in vivo	Yoou et al., 2016b
26	Tannic acid	Decrease of TSLP and cytokine expressions via caspase-1/NF-kβ and alleviation of clinical AD-like symptoms.	Caesalpinia spinosa	In vitro & in vivo	Jung et al., 2010; Kim et al., 2018
27	Vanillic acid	Inhibition of allergic symptoms via blocking NF-kβ and MAPK signaling pathway.	Angelica Sinensis	In vitro	Jeong et al., 2018b
	Lignans
28	(+)-galbelgin	Effective against pSTAT5 and TSLP/TSLPR interactions in both in vitro assays (STAT5 test and ELISA assay), the remaining two also	Machilus thunbergia	In vitro	Shin et al., 2021
29	Machilin A		Machilus thunbergia		Shin et al., 2021
30	Meso-dihydroguaiaretic acid		Machilus thunbergia		Shin et al., 2021
31	Astragaloside IV	Improve allergic symptoms by suppression of pro-allergic cytokine expression.	Astragalus membranaceus var mongholicus	In vitro & in vivo	Zhang et al., 2015; Bao et al., 2016a
32	Atractylenolide III (ATL-III)	Inhibition of mast cell proliferation and decrease the production of TSLP-induced proinflammatory cytokines.	Atractylodes japonica	In vitro	Yoou et al., 2017
33	Atractylone	Suppression of mast cell activation and chemokine production.Alleviation of clinical allergic symptoms in vivo	Atractylodes macrocephala	In vitro & in vivo	Kim et al., 2016
	β-sitosterol	Inhibition of TSLP production by Ca2+/caspase-1/NF-kβ pathway.	Sambucus chinensis	In vitro & in vivo	Han et al., 2014b
35	Deacetylasperulosidic acid	Inhibition of cytokine production via blocking NF-kβ and MAPK signaling pathway and restoring clinical AD-like symptoms.	Morinda citrifolia	In vitro	Oh et al., 2021aOh et al., 2021b
36	Ginsenoside Rh2	Inhibition of TSLP expression and ameliorated AD-like skin symptoms by NF-kβ pathway.	Panax ginseng	In vitro & in vivo	Ko et al., 2019
37	Ursolic acid	Decrease TSLP expression by intracellular Ca2+ level regulation and NF-kβ signaling pathway.	Camellia sinensis	In vitro	Moon et al., 2019
38	(-)-loliolide	Suppression of cytokines expression by downregulation of NF-kβ and MAPK pathway and upregulation of Nrf2-/HO-1 signaling pathway.	Fumaria officinalis L.	In vitro & iin vivo	Han et al., 2021a

STAT5: Signal transducer and activator of transcription 5, LPS: Lipopolysaccharide, MDM2: mouse double minute 2, PLC-r: phospholipase C gamma, HIF1-a: Hypoxia-Inducible Factor 1-alpha, GATA3: GATA-binding protein 3, EGR-1: early growth response 1, HO-1: Heme oxygenase-1.

Alkaloids

Alkaloids are naturally occurring organic compounds characterized by at least one nitrogen atom and basic properties. Here, we emphasize a selection of alkaloids which target TSLP pathways for the treatment of allergic diseases (Fig. 2A).

Figure 2. Compounds with anti-allergic activity targeting TSLP pathways. (A) Alkaloids; (B) Flavonoids; (C) Phenolics; (D) Lignans; (E) Terpenoids and their derivatives.

Berberine

Berberine, a yellow-colored alkaloid effectively suppressed the NF-κB activity induced by phorbol myristate acetate and A23187. In addition, berberine inhibits the activation of caspase-1 in HMC-1 cells. Moreover, it effectively inhibits the production of TSLP in primary mast cells. These findings suggest that berberine has potential therapeutic benefits in treating inflammatory and atopic diseases by targeting TSLP inhibition (Kim et al., 2015a)

Neferine

Neferine has been found to have AD related preventive anti-inflammatory activity in in vitro and in vivo experiment. Neferine suppressed expression of inflammatory cytokines and ameliorated AD-like symptoms via regulation of skin moisturization and MAPK/NF-κB signaling pathway, using human keratinocyte (HaCaT) cells. Additionally, neferine suppressed swelling of spleen, a largest lymphatic organ which can be enlarged by inflammation (Yang et al., 2021).

Tryptanthrin

Tryptanthrin, a plant alkaloid with indoloquinazoline moiety, might be a potential drug for mast cell mediated allergic disease. In in vitro experiment, Tryptanthrin inhibited mast cell proliferation by downregulating the expression of MDM2, a negative regulator of p53, which is activated by TSLP and induces mast cell tumorigenesis, by using human mast cell line (HMC-1) cells. Also, IL-13, a cytokine which promotes mast cell proliferation were decreased by tryptanthrin. Furthermore, it regulated the TSLP signaling pathway by decreasing the expression of IL-7Rα (IL-7 receptor alpha chain) and TSLPR (Han et al., 2016).

Flavonoids

Flavonoids are plant-derived natural compounds showing diverse pharmacological activities, which generally consist of two phenolic rings and one heterocyclic ring. In this work, we suggested a group of flavonoids which is associated with TSLP regulation for the treatment of AD (Fig. 2B).

Acteoside

Acteoside, also called as verbascoside, can be potent therapeutic for AD by regulating mast cell proliferation and apoptosis. MDM2, a negative regulator of p53 target, is activated by TSLP and induces mast cell tumorigenesis. And TSLP also activates STAT5/STAT6 signaling pathway to promote mast cell development. Acteoside suppressed mast cell proliferation by blocking MDM2 and STAT signaling pathway. TSLP-stimulated HMC-1 cells exhibit an upregulation of anti-apoptotic factors and a downregulation of apoptotic factors such as caspase-3. Acteoside induced apoptosis of mast cells by regulation of bcl-2 and caspase-3 (Yoou et al., 2015).

Baicalein

Baicalein, an essential compound derived from Scutellaria baicalensis, is the first small molecule capable of blocking TSLP signaling. Additionally, in vivo and in vitro studies have shown that baicalein effectively inhibits TSLP signaling pathway by blocking the interaction of TSLP and its receptor, TSLPR (Zhu et al., 2021). Also, baicalein inhibited type 2 immune response by suppression of STAT5, which is activated by TSLP signaling pathway (Park et al., 2019a).

Epigallocatechin-3-O-gallate (EGCG)

EGCG, generally referred to as a potent antioxidant, is a primary bioactive constituent found in green tea. Many reports demonstrated its inflammatory activity. In HMC-1 cell line, EGCG suppressed NF- κB activity by inhibiting caspase-1, a special caspase family protein which is responsible for the maturation of IL-1β and IL-18 and activating NF-κB signaling pathway. EGCG decreased the production and mRNA expression of TSLP through blocking NF- κB signaling pathway. So EGCG can be a potential therapeutics for TSLP induced allergic disease (Moon et al., 2012a).

Eupatilin

Eupatilin, a lipophilic flavonoid, can be a valuable candidate as an anti-allergic agent. Eupatilin demonstrates beneficial effects in a mouse model of AD-like symptoms induced by oxazolone. It effectively reduced the expression of inflammatory cytokines and recovered skin damage by increasing the production of skin structural proteins (Jung et al., 2018).

Fisetin

Fisetin, a bioflanonol abundant in fruit and vegetables, has reported to possess anti-inflammatory activity. It suppressed histamine release and expression of inflammatory markers like COX-2 and IL-4 in vitro. In in vivo study, fisetin alleviated not only LPS-induced inflammation but also the clinical symptoms of AD. Fisetin reduced ear swelling and epidermal thickness in DNFB-treated mice. And it also inhibited infiltration of inflammatory cells into skin lesions and cytokine productions (Kim et al., 2014).

Formonectin

Formonectin (FMN), an isoflavone phytoestrogen, exhibits a protective effect in allergic diseases in vivo and in vitro. FMN inhibits DC activation which leads to T cell differentiation. FMN is associated with the downregulation of TSLP/IL-33 production through GPER (G protein-coupled estrogen receptor) signaling pathway (Yuan et al., 2020). It also upregulates the expression of the A20 (TNFAIP3) protein, a regulator of immune cell function in airway allergic disease. A fluorescein isothiocyanate (FITC)-induced mouse model and Human keratinocytes (HaCaT) cells were used in such experiment (Yuan et al., 2021).

Kaempferol

Kaempferol is a natural flavonol having antioxidant and anti-inflammatory effects. In vitro, Kaempferol suppressed the production of proinflammatory cytokines by inhibition of MAPK and NF-κB signaling pathway. It also had a cytoprotective effect by suppression of the LPS (lipopolysaccharide)-induced production of inflammatory mediators. Additionally, kaempferol inhibited the differentiation of monocytes into macrophage-like cells. A human monocyte cell line THP-1 was used in this experiment (Nam et al., 2017).

Naringenin

A flavonoid aglycone abundant in grapefruit, naringenin, exhibits a significant inhibitory effect on TSLP production via NF-kβ activity downregulation (Moon et al., 2011). It also suppressed cell proliferation and induce apoptosis in mast cells by reducing the protein level of MDM2 and pSTAT6, while upregulating cleaved poly ADP-ribose polymerase (PARP) and p53 levels in TSLP-induced HMC-1 cell. As a result, naringenin inhibited the cytokine production and inflammation (Han et al., 2018).

Quercetin

Quercetin, a famous antioxidant, showed wound healing effect in inflamed state. Quercetin suppressed cytokine production by MAPK and NF-κB pathway in vitro by using Immortalized human HaCaT keratinocytes (Beken et al., 2020), and also decreased IgE and cytokine levels in vivo (Sozmen et al., 2016b). It inhibited inflammatory cell infiltration and also regulated mast cell degranulation by PLC-γ2 pathway (Gupta et al., 2016). Quercetin provides a notable option to treat airway inflammation.

Saponarin

Saponarin, a flavone glycoside mainly obtained from barley, significantly inhibits inflammatory and allergic responses in various cell lines (RAW 264.7, RBL-2H3, and HaCaT Cells). It showed inhibitory activity on cytokine production through MAPK signaling pathway. It suppressed the expression of inflammatory mediators like COX-2 and suppressed chemokine expressions. It also protects skin by maintaining moisture and physicochemical barriers by upregulation of hyaluronan synthase-3 (HAS3), aquaporin 3 (AQP3) (Min et al., 2021).

Phenols

Phenolic compounds, natural bioactive substances synthesized through shikimic acid and phenylpropanoid pathway, are found abundantly in fruits and vegetables. Here, we highlighted several phenolics, which have been reported as inhibitors of TSLP derived from medicinal plants (Fig. 2C).

Calycosin

Calycosin is a phytoestrogen, supposed to have a potential therapeutic candidate for AD. It improved epithelial tight junction by inhibiting the expression of HIF1-α, increasing epithelial permeability and upregulated under allergic condition in vivo and in vitro (Jia et al., 2018). It also reduced the production of TSLP and IL-33 by inhibiting the TLR4 mediated NF-κB signaling pathway. In vivo, mice were just sensitized with FITC (fluorescein isothiocyanate), and immortalized human keratinocytes (HaCaT cells) were used in vitro (Tao et al., 2017).

Catechin

Catechin, famous for its anti-inflammatory activity, might be a good treatment for nasal allergy. Catechin decreased TSLP production by blocking phosphorylation of NF-κB p65 signaling pathway in vitro. In in vivo experiment, catechin reduced clinical symptoms of nasal allergy in allergic rhinitis mouse model. The counting of sneezing and nose rubbing behavior was decreased. Additionally catechin reduced cytokine levels in the serum and modulated the balance between T helper type 2 and T helper type 1 cells (Pan et al., 2018b).

Chrysin

A 5,7-dihydroxyflavone, chrysin is reported to decrease the production of inflammatory cytokines via MAPK and NF-κB signaling pathways in in vivo and in vitro experiment using HaCaT keratinocytes. Especially, chrysin inhibited ERK1/2 and JNK1/2-mediated EGR-1 (early growth response 1) expression, a transcription factor which induces TSLP production under inflamed state (Yeo et al., 2021a).

Chrysophanol

Chrysophanol, a unique anthraquinone isolated from fungi, is reported to exert various biological activities. Chrysophanol inhibited various cytokines expressions by inhibiting caspase-1, NF-κB and MAPK signaling pathway in vitro (Jeong et al., 2018a). It also prevented and the production of TSLP by blocking TSLP and TSLPR interaction (Kim et al., 2019a). In in vivo study, it alleviated clinical allergic symptoms while inhibiting the proliferation of mast cells via regulation of MDM2/p53 and caspase-3/Bax/Bcl-2 signaling pathway (Han et al., 2019)

Cimifugin

Cimifugin, an effective compound found in Saposhnikovia divaricate, is used as medicine for anti-inflammatory disease. In mice atopic dermatitis model, it alleviated AD symptoms via regulating tight junction deficiency by increasing tight junction gap protein expression. Also in vitro study, tight junction protein expressions like CLDN-1 and OCC were increased by cimifugin. Also, TSLP and Th2 cytokine production was suppressed. This process attenuates the development of allergic inflammation, so cimifugin might have potential of targeting primary cytokines and TJs for therapeutic intentions. FITC mice and immortalized human epidermal (HaCaT) cells were used in this study (Wang et al., 2017).

Curcumin

Curcumin, a main constituent from tumeric, is known as a strong anti-inflammatory agent. Curcumin reduced LPS-induced NO production in vitro (Ben et al., 2011). It suppressed the expression of TSLP and Th2-cytokines via downregulation of caspase-1/NF-κB and STAT6/GATA3 signaling pathway in vivo and in vitro. In mice, inflammatory cell infiltration was decreased, and redox imbalance was restored under airway inflamed state (Sharma et al., 2019).

Eckol

Eckol, one of phlrotannins isolated from marine brown algae Ecklonia cava (EC), has potential for drugs of AD. It was reported that eckol from EC inhibited the activation of MAPKs and NF-κB signaling pathway by hindering the TNF-α/IFN-γ-mediated nuclear translocation of NF-κB p65 in HaCaT cells. It also inhibited MAPK signaling pathway, which consequently suppressed mRNA expression of proinflammatory cytokines and chemokine production (Cho et al., 2020).

Ferulic acid

Ferulic acid (FA) inhibits an allergic Th2 response by effectively decreasing key features of allergic markers in vivo (Brugiolo et al., 2017b). FA decreased inflammatory cytokines and chemokines via inhibition of NF-κB signaling pathway. Also, it suppressed Th2 immune response and regulated the filaggrin upregulation (Zhuo et al., 2020, Brugiolo et al., 2017b). Additionally, FA mitigates allergic symptoms by decreasing infiltration of inflammatory cells and restoring the balance of Th2 cell proliferation. For the in vivo, ovalbumin- (OVA-) induced Th2-mediated allergic mice was used, and for the in vitro antigen-presenting dendritic cells (DCs) was used in this study (Lee et al., 2015).

Licochalcone A

Licochalcone A is a chaloconid, a natural phenol exhibiting anti-inflammatory activity in vitro. Licochalcone A suppressed the expression and production of TSLP and various proinflammatory mediators. It showed the inhibitory effect on IKK activity, and also inhibited NF-κB nuclear translocation and DNA-binding activity by using BEAS 2B cells and primary bronchial epithelial cells. So Licochalcone A could be a prominent option for treatment of asthma (Kim et al., 2015b).

Manoalide

Manoalide, a marine sesterterpenoid famous for a calcium channel blocker, has been known for its anti-cancer and super oxide scavenging activity. In HMC-1 cells, it prevented the secretion of various inflammatory cytokines without cytotoxic effects by inhibiting caspase-1 activity. Furthermore, manoalide treatment effectively inhibited mast cell stimulation by blocking NF-κB and MAPK signaling pathway. So it seems that manoalide can be potential candidate for allergic disease treatment (Yeom et al., 2021).

Resveratrol

Resveratrol, a stilbenoid antioxidant, demonstrates well known anti-inflammation activity. In in vivo experiment, resveratrol mitigated inflammation severity by decreasing expression of keratinocyte derived cytokines in AD-like skin lesions. Also, resveratrol ameliorated thickening and irregularity of mice epidermis skin via controlling keratinocyte derived apoptosis (Sozmen et al., 2016a).

Rosmarinic acid (RA)

Rosmarinic acid (RA) effectively reduced TSLP-induced mast cell proliferation by decreasing the expression of MDM 2 and pSTAT6 in vitro. RA also modulated mast cell apoptosis via regulating apoptotic marker expression, inducing PARP cleavage by p53 and caspase 3 activation and reducing procaspase-3 and Bcl-2, and in vivo experiment, it inhibited inflammatory molecules production through TSLP signaling pathway (Yoou et al., 2016b).

Tannic acid

Tannic acid (TA), a polyphenol natural product with bitter taste, effectively suppressed TSLP and various inflammatory cytokine expressions by inhibition of caspase-1, NF-κB and MAPK signaling pathways in vitro (Jung et al., 2010). TA also might be associated with VEGF signaling pathway, a regulator of permeability of epithelial cells and overexpressed in AD-like symptoms. In in vivo experiment, TA decreased clinical AD-like symptoms (Kim et al., 2018).

Vanillic acid

Vanillic acid, a benzoic acid derivative widely used as flavoring agent, ameliorated allergic response by controlling MAPK and NF-κB signaling pathway. MAPK signaling pathway has been established an important role in controlling inflammatory gene expression. In HMC-1 cells, VA reduced the levels of TSLP and proinflammatory cytokines via inhibition of MAPK signaling pathway. Furthermore, vanillic acid significantly inhibited development of allergic response by blocking caspase-1 and NF-κB signaling pathway (Jeong et al., 2018b).

Lignans

Lignans are known for their antioxidant and potential health-promoting properties. Lignans also inhibit the TLSP. Three lignans, specifically (+)-galbelgin, meso-dihydroguairetic acid, and machilin A, (Fig. 2D) isolated from Machilus thunbergia, function as antiallergic bioactive substances. All three compounds shown significant inhibitory effect against pSTAT5 and TSLP/TSLPR interactions in both in vitro assays (STAT5 test and ELISA assay) and in silico assays. (+)-galbelgin and meso-dihydroguairetic acid exhibited potent pSTAT5 inhibitory actions of 54.5% and 64.1%, respectively, in HMC-1 cells stimulated with hTSLP. Furhtermore, (+)-galbelgin displayed over 20% inhibition of hTSLP–hTSLPR interaction at 0.3 mM. Taken togther, these lignins acts as a strong TLSP Inhibitors (Shin et al., 2021)

Terpenoids

Terpenoids is natural compounds synthesized from five-carbon isoprene building blocks, and they exhibit diverse biological activities. In this study, we highlighted several derivatives of terpenoids acting as inhibitors of TSLP derived from medicinal herbs (Fig. 2E).

Astragaloside IV

Astragaloside IV (AS-IV) is a tetracyclic triterpene glycoside mainly found in Astragalus membranaceus, showing preventive effect for treatment of allergic disease. In an in vitro study, AS-IV significantly mitigated the allergic inflammation by reducing pro-allergic cytokine production (Bao et al., 2016b). In vivo, AS-IV administration during the early stages alleviated inflammatory response by reducing ear swelling and suppression of Th2 cytokine expressions, by using human peritoneal mesothelial cells (HMrSV5) (Zhang et al., 2015).

Atractylenolide III

A sesquiterpenoid widely used as anti-cancer agent, atractylenolide III (ATL-III) decreased TSLP-stimulated cytokine production. ATL-III suppressed the TSLP-induced proliferation of mast cells by regulation of MDM and pSTAT6 signaling pathway. Moreover, ATL-III induce mast cell apoptosis by decreasing Bcl-2 and increasing procaspase-3 expression (Yoou et al., 2017).

Atractylone

Atractylone (Atr), a sesquiterpenoid known as effective antioxidant, is reported to alleviate clinical allergic symptoms in vitro and in vivo. Atr effectively suppressed mast cell activation by blocking caspase-1, MAPK, NF-κB signaling pathway in vitro. In mice, Atr reduced histamine release and expression of allergic markers inducing itching nose. Furthermore, Atr mitigate the infiltration of inflammatory cells into nasal mucosa tissues with inhibition of caspase-1 pathway (Kim et al., 2016).

β -Sitosterol

β-sitosterol (BS) is one of phytosterols, known for its antioxidant and anti-inflammatory activity. BS inhibited TSLP production by inhibition of Ca²⁺/ caspase-1 and NF-κB pathway in vitro. In mice, expression of inflammation-related markers and caspase-1 activity was suppressed by BS administration. It also inhibited the infiltration of inflammatory cells into skin lesions and alleviated the scratching behavior (Han et al., 2014b).

Deacetylasperulosidic acid

Deacetylasperulosidic acid (DAA), a monoterpene glycoside mainly found in Morinda citrifolia, exerts antioxidant activity. In in vitro study, DAA inhibited the production of cytokines via MAPK and NF-κB signaling pathways. It also decreased histamine release by inhibiting IκBα decomposition (Choi et al., 2016; Kim et al., 2020; Oh et al., 2021b). Additionally, DAA relieved clinical AD-like symptoms by controlling immune balance and recovering skin barrier function in vivo in 2,4-Dinitrochlorobenzene-Induced atopic dermatitis NC/Nga Mice (Oh et al., 2021a).

Ginsenoside Rh2

Ginsenoside Rh2 (Rh2), a triterpenoid saponin exerts anti-inflammatory activity. In an in vivo and in vitro study, Rh2 showed the strongest inhibitory activity on TSLP expression when compared to other ginsenoside compounds. In mice experiment, Rh2 ameliorated AD-like skin symptoms by inhibition of the NF-κB pathway and inflammatory cell infiltration. Additionally, Rh2 suppressed the differentiation of naïve CD4⁺ T cells into T helper type 2 cells (Ko et al., 2019).

Ursolic acid

Ursolic acid (UA) is a natural triterpene showing a preventive effect for AD treatment in in vitro study. UA inhibited mast cell activation by regulation of intracellular Ca²⁺ concentrations, which activates caspase-1, a trigger of NF-κB signaling pathway. Consequently, UA suppressed TSLP expression and production by inhibition of Ca²⁺/caspase-1/NF-κB axis (Moon et al., 2019).

(-)-Loliolide

(−)-Loliolide (LO), a monoterpene lactone possessing various beneficial bioactivities, effectively reduced the expression of initial cytokines such as IL-25, IL-33, and TSLP, which lead to chemokine production. LO is supposed to have cytoprotective role under inflamed condition by inhibiting MAPK and NF-κB signaling pathways while activating the Nrf2/HO-1 signaling pathway, in IFN-γ/TNF-α-Stimulated HaCaT Keratinocytes (Han et al., 2021a).

The current clinical and basic studies emphasize the benefits of using naturally occurring substances with fewer or no adverse effects (Newman, 2021). This review summarizes the naturally occurring compounds that inhibit allergy associated with TSLP pathways. In conclusion, we hypothesize that the TSLP inhibitors can be potential novel targets with a definite advantage in drug development for treating allergic diseases. Moreover, TSLP stimulates immune cells such as dendritic cells to release inflammatory cytokines, thereby contributing to increased airway inflammation. Furthermore, TSLP facilitates the proliferation of immune cells, especially Th2 cells, pivotal in the progression of asthma. By influencing the respiratory mucosa, TSLP heightens sensitivity and establishes an environment conducive to inflammation, thereby contributing to the pathogenesis of asthma (Fig. 3).

Figure 3. TSLP promotes Th2-driven immunity, amplifying allergic responses and contributing to asthma progression, modified from (Ebina-Shibuya and Leonard, 2023). DC: Dendritic cell, TSLP: Thymic stromal lymphopoietin, ILC2: Group 2 innate lymphoid cells.

This review extensively draws data cellular and animal experiments to evaluate the efficacy of medicinal plants and naturally occurring compounds that inhibit allergy via targeting the TSLP pathway. In general, using traditional medicinal plants to treat allergies is interesting, resulting in the development of conventional medicinal plant mixture-based medicines for controlling allergic diseases, e.g., YPFS, Madi-Ryuk, and HLJDD (Table 1). Apart from studies of plant extracts’ anti-allergic effects, natural compounds’ anti-allergic effects are investigated, with the main classes being terpenoids, flavonoids, alkaloids, phenol, phenolic acids, and ligands (Fig. 4A). The extracts and compounds exhibit sound anti-allergic effects by targeting TSLP pathways in vitro and/or in vivo studies, warranting further investigations in preclinical and clinical trials.

Figure 4. Distribution of (A) Phytochemicals; (B) Natural Products Extracts with Anti-Allergic Activity via Targeting TSLP Pathways.

Plants are the main sources of investigations as they produce anti-allergic substances that target TSLP pathways, with 78 genera belonging to 50 families (accounting for 91%). However, only a few investigations have been performed to date that evaluate the roles of anti-allergic effects via targeting TSLP pathways from other sources, i.e., fungi, bacteria, algae, and seaweeds (Fig. 4B). This observation implies that there may still be anti-allergic agents targeting TSLP pathways from other potential sources that have not been explored. Marine-derived natural products are a prolific source of potential anti-allergic compounds with diverse structures (Kim et al., 2011; Xie et al., 2017). Investigation of anti-allergic compounds targeting TSLP pathways from the marine environment may be a potential source for anti-allergy agents.

This review reveals that several plant extracts, such as KRG, Astragali Radix, and Polygonum tinctorium, and their mixtures (traditional medicine formula) exhibit allergy inhibitory effects via targeting TSLP pathways under in vitro and/or in vivo studies (Table 1). However, the critical components responsible for their anti-allergic effects have not yet been studied. Discovering the potential main components may help develop anti-allergy drugs. Also, several natural products derived from plants (Table 2) have anti-allergic effects and should be considered for further studies in vivo, preclinical, and clinical trials. Furthermore, synthesis and semisynthesis of anti-allergic agents based on lead compounds from natural sources should be attempted to develop anti-allergic agents.

Natural bioactive compounds from plants have traditionally been utilised to combat various diseases, and contemporary techniques are now being employed to address the challenge of combating life-threatening illnesses using these sources. Virtual screening techniques have significantly improved the capacity to utilise computational methods for discovering pharmacological candidates. Recently, the development of herbal products has been gaining popularity. We previously identified that lignans isolated from M. thunbergia significantly inhibit STAT5 phosphorylation and the interaction between TSLP and TSLPR, as determined by ELISA (Shin et al., 2021). Additionally, the protein with PDB-ID: 5J11 provides the structure of human TSLP in complex with TSLPR and IL-7Ralpha (Shin et al., 2021). These studies confirm the importance of treating allergic diseases, which can be applied in future experiments. Virtual screening can validate the interaction of bioactive compounds with human TSLP in complex with TSLPR and IL-7Ralpha. Thus, in our efforts to evaluate the potential of TSLP inhibitors in this review, we conducted molecular docking to assess 47 natural compounds as ligands for human TSLP in complex with TSLPR and IL-7Ralpha. Based on the docking calculations, compounds (1-47) exhibited binding energies ranging from – 3.464, and – 8.256 kcal/mol, respectively (Table 3). Therefore, the binding energies of the compounds could aid in understanding the potential for discovering pharmacological candidates that inhibit the TSLP pathway.

Table 3 Docking scores of natural product compounds (1-46) targeting TSLP pathways with anti-allergic activity are presented. The structure of human TSLP bound to TSLPR and IL-7Ralpha (PDB-ID: 5J11) was provided by the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB). The protein structure was minimized using the OPLS4 force field until the average root-mean-square deviation (RMSD) of the heavy atoms reached 0.3 Å. This was accomplished using the protein preparation tool in Maestro v12.4. The 2D structures of the ligands were transformed into 3D structures using the LigPrep tool. This process aimed to obtain geometry-optimized structures at pH 7.0 ± 2.0 while considering the chirality of the ligand based on its 3D structure. The concluding stage of LigPrep involved energy minimization of the 3D conformers through the utilization of the OPLS4 method. Docking and calculations were performed using the standard precision (SP) mode of the Glide software

Compounds	Docking scores	Compounds	Docking scores	Compounds	Docking scores
1	–6.566	16	–6.249	31	–5.431
2	–6.047	17	–5.932	32	–7.375
3	–7.590	18	–6.551	33	–4.551
4	–6.821	19	–7.215	34	–6.117
5	–6.782	20	-	35	–4.182
6	–7.366	21	–5.427	36	–4.552
7	–8.068	22	–6.783	37	–5.417
8	–6.004	23-1	–4.910	38	–4.468
9	–8.256	23-2	–5.301	39	–4.021
10	–7.589	24	–5.043	40	–6.559
11	–6.165	25	–5.402	41	–5.463
12	–6.429	26	–5.435	42	–6.417
13	–6.624	27	–5.493	43	–3.954
14	–6.028	28	–6.688	44	–5.412
15	–6.096	29	–5.163	45	–3.464
		30	–6.000	46	–4.807

(-) NT.

In summary, numerous phytochemicals obtained from natural sources offer significant benefits compared to synthetic drugs, primarily due to their biocompatibility and reduced likelihood of toxic side effects. Furthermore, these natural bioactive compounds demonstrate significant efficacy by targeting multiple pathways and are also effective in modulating complex biological processes such as TSLP. Additionally, these natural bioactive compounds are linked to minimal side effects, as they are primarily compatible with the body’s environment. The characteristics of phytochemicals position them as promising options for creating therapies focused on regulating TSLP and alleviating allergic reactions. This review outlines the extracts and naturally occurring compounds recognized for their ability to inhibit allergies linked to TSLP pathways, suggesting their promising role in advancing drug development for allergic disease treatment.

This research was supported by the National Research Foundation of Korea grants funded by the Korean Government (NRF-2019R1A6A1A03031807 and NRF2021R1A2C1093814) and the MSIT (Ministry of Science and ICT), Korea under the ITRC (Information Technology Research Center) support program (IITP-2024-RS-2023-00258971) supervised by the IITP (Institute for Information & Communications Technology Planning & Evaluation).

The authors declare that there are no conflicts of interest.