Skin pruritus is caused by both histamine and non-histamine mechanisms (19). Keratinocytes create pruritogens locally, which move to the skin through the circulation pathway and activate sensory nerve endings (20). The peripheral nerves are classified into three types: i) Aβ fibers (myelinated and mechanosensitive); ii) Aδ fibers (thinly myelinated); and iii) C fibers (unmyelinated) (11). Itch signals are primarily transmitted by Aδ/C fibers (11). The histamine system employs histamine receptors, whereas the non-histamine pathway is activated by a number of pruritogens that target specific receptors (21). These two pathways join, using Mas-related G protein-coupled receptor (MRGPR) signaling to construct a dual regulatory network (22) (Fig. 1). Pruritus-related biochemical receptors interact with G protein-coupled receptors (GPCRs; main subtypes) or the Janus kinase (JAK)/STAT pathway (cytokine/chemokine receptors) to activate TRP and NaV channels, resulting in action potentials (11). These impulses are then transmitted to the spinal cord through ascending channels to the brain (23), causing the sensation of pruritus (Fig. 2).

MRGPRs are primary regulators of non-histamine-dependent pruritus, with pruritogens activating a number of pathways [Gq protein-coupled signaling cascades (24), Gi protein signaling pathways (25), calcium mobilization and calcium-dependent pathways (26,27) and TRP ion channel signaling routes (28)] (Fig. 3). The rodent MRGPRA/B/C and primate MRGPRX subfamilies are particularly important in this area of pruritus research (29).

Chloroquine (CQ) treatment in patients with malaria in Africa frequently causes intense pruritus (30). A study showed that mice lacking a cluster of 12 MRGPR genes exhibit reduced scratching after CQ administration, indicating that MRGPR-expressing neurons contribute to itch perception (31). CQ directly activates MRGPRA3, and ablation of MRGPRA3-expressing neurons [which constitute 5–8% of dorsal root ganglion (DRG) neurons] alleviates both acute and chronic itch symptoms (31). These findings have established MRGPRA3 as a specific marker for neuronal pentraxin 2-positive pruriceptive neurons.

Bovine adrenal medulla (BAM)-8-22 and γ2-melanocyte stimulation hormone can activate human MRGPRX1 and mouse MRGPRC11, which are orthologous receptors (32,33). BAM8-22 is a strong agonist for both. Furthermore, activation of MRGPRC11/X1 elicits varying effects depending on the site of action. Namely, subcutaneous activation of cutaneous sensory fibers causes itching (31), whereas intrathecal activation causes analgesia (34,35). As a result, an improved understanding of the functional roles of MRGPRC11/X1 is required to create targeted therapeutic strategies for pain- and itch-related diseases.

MRGPRD is expressed in small-diameter DRG and trigeminal ganglion neurons (36). Its positive fibers are non-peptidergic, unmyelinated, mechanosensitive C-fibers that densely innervate the skin (37). β-alanine is a natural ligand for MRGPRD (38) in both humans and mice and directly activates this receptor, inducing itch in numerous individuals. Neurons from MRGPRD-knockout mice exhibit no response to β-alanine (39). In addition, in a model of atopic dermatitis (AD), the excitability of MRGPRD⁺ neurons was increased (40), suggesting a role for MRGPRD in both acute and chronic itch (41).

MRGPRB2 and its human ortholog MRGPRX2 are specifically expressed in connective tissue mast cells and may be activated by exogenous drugs or endogenous neuropeptides such as substance P (SP) (42,43). Activation of MRGPRB2 primarily triggers mast cell release of tryptase, which in turn drives non-histaminergic itch pathways (44–46). MRGPRX2 expression is upregulated in patients with AD, psoriasis, allergic contact dermatitis and chronic urticaria (47). In disease models, MRGPRB2-deficient mice exhibited markedly reduced itch and inflammation symptoms (48,49), highlighting MRGPRX2 as a promising therapeutic target for allergic pruritus.

Elevated bile acid levels in the serum of patients with cholestatic disorders are associated with non-histaminergic pruritus (50). Bile acids can directly activate MRGPRX4 at physiological concentrations (51). Genetic deletion of its murine ortholog, MRGPRA1, markedly reduces scratching behavior in mice (52), whereas transgenic mice expressing human MRGPRX4 exhibit exacerbated scratching in both acute and chronic cholestasis models (53). These findings indicate that MRGPRX4 is a potential therapeutic target for alleviating cholestasis-associated itch.

PARs act as a regulatory center, combining protease signaling and epidermal barrier failure. Kallikreins and mast cell-derived tryptase activate PAR2 and 4, resulting in pruritus. Mast cell tryptase stimulates PAR2 through the phospholipase C-β/inositol trisphosphate pathway, leading to IL-31 release and keratinocyte production of thymic stromal lymphopoietin (TSLP). This signaling cascade decreases filaggrin production through the ERK/JNK/MAPK pathway. PAR2 activation further causes mast cell degranulation, which releases cytokines that directly activate nerve terminals, resulting in a self-amplifying pruritic cycle (44,54,55). In an animal study, administration of the PAR2 inhibitor PA-235 has been shown to markedly reduce pruritic behaviors. Single-cell sequencing results continue to show that PAR2 expression levels in patients with AD lesional skin are positively associated with ‘SCORing Atopic Dermatitis’ scores (56,57). Furthermore, Staphylococcus aureus serine protease V8 directly activates PAR1 on sensory neurons, causing bacterial infection-induced itching (58).

Upon TLR detection of molecular patterns associated with infection or damage, inflammatory signaling through the myeloid differentiation primary response 88 (MyD88)/IL-1 receptor-associated kinase (IRAK)/TNF receptor-associated factor 6 (TRAF6) axis is activated. This activates the IKK complex, transports NF-κB to the nucleus and promotes pro-inflammatory gene transcription (59,60). Activation of the MAPK (ERK/p38/JNK) pathway further initiates the production of cytokines (TNF-α, IL-1/6/12, IL-8 and macrophage inflammatory protein-2) as well as reactive oxygen/nitrogen species (61–63). These mediators are produced by immune cells and astrocytes, inducing local neuroinflammation and the transmission of pruritic signals (64,65) (Fig. 3).

DRG neurons that express TLR3/TRPV1 drive both histaminergic and non-histaminergic acute itching (66), as evidenced by agonist-induced scratching behavior in mice. Notably, isothiocyanates (including phenethyl isothiocyanate and sulforaphane) markedly reduce poly(I:C)/CQ-induced acute itch and oxazolone-induced chronic itch via inhibition of the TLR3 pathway (67).

TLR4 is located in the DRG, trigeminal ganglia and spinal glia (68), regulating both acute and chronic pruritus. TLR4 markedly improves histamine-dependent signaling in acute itch by raising TRPV1 activity but has little effect on CQ- or compound 48/80-induced reactions (69). Chronic stressors, such as dry skin, activate TLR4 in spinal astrocytes via the STAT3/lipocalin 2 axis (70,71); however, intrathecal TLR4 suppression markedly diminishes these responses (70,71). Psoriasis-associated human β defensin-2 activates cutaneous macrophage TLR4 (72), resulting in inflammatory itch, whereas TLR4 inhibition reduces neurosensitization and T helper 2 (Th2)/innate immune factor release (73).

TLR5, unlike other TLRs expressed in small-diameter neurons, is predominantly expressed in medium-to-large DRG neurons (74) corresponding to Aβ-LTMRs, which mediate mechanical pruritus through activation of spinal urocortin 3-positive interneurons (75).

TLR7, which is expressed in DRG neurons with TRP ankyrin (TRPA)-1, is a key regulator of histamine-independent itch (76–78). Ligands such as imiquimod directly activate DRG neurons, causing scratching behavior and mediating chronic itch through TRPA1-dependent processes (79). Let-7b, a secreted extracellular microRNA, acts as an endogenous TLR7 ligand, contributing to pruriceptive signaling (80). TLR2 and TLR7 on epidermal keratinocytes promote the release of chemokine C-X-C motif ligand-1/2, IL-31, IL-33, IL-17A and TNF-α, which contribute to chronic itching in dry skin and psoriasis (81). Let-7b inhibits psoriatic epidermal differentiation by downregulating IL-6 and inhibiting ERK1/2 (82).

NaV channels control the intensity and duration of itch signals by altering the action potential threshold (102,103): Higher NaV channel activity increases neuronal excitability by lowering the action potential threshold, resulting in more frequent action potentials and enhanced pruritic signal intensity. The inactivation kinetics of NaV channels determine the duration of action potentials: slower inactivation prolongs action potential duration, sustaining pruritic signals, whereas faster inactivation shortens action potentials, leading to transient pruritic signaling. A study employing sodium channel-specific knockout mouse models (104) have shown that NaV1.7 and NaV1.9 are primarily involved in acute pruritic signaling, while NaV1.8 is associated with persistent itch pathogenesis. Additional research (105) has revealed that DA-0218, a computationally developed high-selectivity NaV1.7 inhibitor, reduced both nociception and pruritus in animal models. This drug exhibited broad-spectrum efficacy in inflammatory pain and lymphoma-induced persistent pruritus, indicating that NaV1.7 may be a suitable target for cross-disease pruritus treatment.

Neuropeptides serve an important role in regulating the homeostasis of the ‘neural-immune-cutaneous’ interaction network (Table II). SP activates the mast cell surface receptors neurokinin 1 and MRGPRX2 (115,116), causing the production of inflammatory mediators such as histamine and tryptase (117,118), resulting in a cycle of neurogenic inflammation and pruritus (16). Calcitonin gene-related peptide (CGRP), which acts as an immunological modulator in AD, stimulates IL-13 production (119). Conversely, fluctuations in IL-13 levels reciprocally influence CGRP release and neuronal sensitization (16). IL-31 activates its receptor IL-31RA to trigger CGRP secretion, while CGRP subsequently suppresses CD4+ T cell proliferation and reduces IL-13 generation, establishing an ‘IL-31→CGRP→IL-13’ negative feedback axis. This axis dynamically modulates type 2 inflammatory intensity and pruritic manifestations (120), with CGRP levels adjusting downstream inflammatory outputs in response to upstream signals, implying a dynamic relationship with pruritus intensity. BNP, a pruritogenic neuropeptide, exhibits increased synthesis and release mediated by IL-31 in the skin tissues and in vitro models of nodular prurigo as well as the inflammatory microenvironment of AD. BNP levels are markedly raised in the lesional skin of patients with AD, where it activates the NPR1 receptor on keratinocytes (121), promoting periostin release and creating a positive feedback loop through the ‘BNP-periostin’ axis. Endothelin (ET)-1 promotes pruritus signaling through the ET-A and ET-B receptor-mediated pathways (122).

Th2 inflammatory axes establish a pruritic signaling amplification system by modulating the ‘neural-immune-epidermal’ interactive network (Table III; Fig. 3). The IL-4/IL-13 axis serves a central role in cutaneous inflammation and pruritus (123–126). IL-31, a pro-inflammatory cytokine secreted by Th2 cells, is a key driver of chronic pruritus when upregulated (127–131). IL-33, a dual-function protein from the IL-1 family, acts as a cytokine binding to the IL-1 receptor-like 1 (ST2) receptor on Th2 cells to regulate IL-17A and IL-31 production as well as induce mast cell degranulation (132). As a nuclear transcriptional regulator, IL-33 interacts with the NF-κB p65 subunit in endothelial cells to facilitate inflammatory response progression (133–136). The IL-23/IL-17 axis is primarily implicated in the pathogenesis of psoriasis, AD and lupus erythematosus (137–139). TSLP serves a pivotal role in amplifying pruritic signaling in inflammatory skin diseases such as AD by activating dendritic cells to drive Th2-type immune responses (140–145).

The expression levels of periostin, an extracellular matrix protein expressed by keratinocytes and fibroblasts, are associated with the pathological course of pruritus (146–148). Concurrently, neurotrophic factors, including nerve growth factor and brain-derived neurotrophic factor, serve a role in pruritic and inflammatory pathologies through distinct neuroimmunomodulatory mechanisms, with a focus on the coordinated regulation of neuronal activation and immune cell chemotaxis, collectively forming a molecular foundation for neurogenic inflammation (149–153) (Table IV).

Endogenous opioids, including β-endorphin and dynorphin A, affect pruritus through GPCRs, specifically the µ-opioid receptor (MOR) and κ-opioid receptor (KOR). MOR is highly expressed in inhibitory interneurons of the spinal dorsal horn, such as NPY+ or Vgat+ neurons. β-endorphin, an endogenous MOR agonist, inhibits the activity of these inhibitory neurons upon MOR activation, thereby lifting their suppression on gastrin-releasing peptide (GRP)-positive pruriceptive neurons (i.e., ‘disinhibition’). This disinhibition hyperactivates the GRP-GRPR microcircuit, amplifying pruritic signal transmission to the brainstem (154,155). Specific knockout of the Oprm1 gene in NPY or Vgat+ neurons completely abolishes morphine-induced pruritus, confirming the central role of this pathway (154,155). Under pathological conditions such as atopic dermatitis, MOR activation upregulates pruritic mediators (e.g., IL-31) and enhances TRP channel activity, intensifying peripheral neuronal sensitization and exacerbating itch perception (156). KOR agonists (e.g., nalfurafine) selectively suppress spinal efferent neurons expressing GRPR projecting to the lateral parabrachial nucleus/lateral spinal nucleus, blocking the transmission of pruritic signals to higher brain centers (157). Activation of the β-endorphin-MOR axis causes pruritus, while dynorphin A-KOR signaling reduces symptoms, creating functionally opposing roles. An imbalance in ligand binding to MOR and KOR in both plasma and the epidermis may exacerbate pruritus in individuals with psoriasis, Alzheimer's disease or liver disease (158–163).

Perceptions of pruritus involve interactions among numerous neural circuits within the brain (172), including the primary somatosensory cortex, thalamus, PBN, central amygdala (CeA), periaqueductal gray and ventral tegmental area (VTA), among other regions (Fig. 4). The PBN constitutes a core hub for itch processing (173), where neurons are activated under histamine and CQ stimulation. Deletion of the glutamate transporter in this region reduces itch-related behaviors (174). The CeA integrates inputs from numerous brain regions to modulate itch-associated affective states. For example, histamine enhances neuronal activity in its projection zones and optogenetic activation of CeA neurons evokes scratching and anxiety-like behaviors (175). The VTA mediates itch-related aversion through γ-aminobutyric acid-ergic neurons, while its dopaminergic neurons are implicated in the rewarding effects of scratching (176). Furthermore, TAC1⁺ neurons in the lateral and ventrolateral periaqueductal gray regulate spinal pruriceptive transmission through the rostral ventromedial medulla pathway (176). Itch perception arises from the coordinated activity of distributed brain networks processing sensory (177), emotional (178) and cognitive components (179); however, the specific neural circuitry mechanisms require further elucidation to guide targeted therapies.

Clinical research on TCM for pruritic disorders (including psoriasis, eczema, urticaria and AD) has primarily focused on integrating disease-based diagnosis with TCM pattern differentiation (190–193). A combined approach of internal and external therapies has demonstrated enhanced efficacy, whereby topical herbal formulations for eczema can precisely modulate immune responses (190), acupuncture or multi-herb formulas for urticaria show high response rates (191), and integrative TCM-Western medicine strategies for psoriasis improve therapeutic outcomes and support early management of comorbidities (192). In the treatment of AD, TCM emphasizes the use of topical herbal washes or ointments (193). These formulations not only alleviate severe itching and skin dryness but also improve skin barrier function, thereby delaying disease recurrence and reducing dependence on corticosteroids (190–193). These interventions not only alleviate symptoms and reduce recurrence but also minimize adverse effects (such as skin atrophy, pigmentation, increased infection susceptibility and relapse after discontinuation, limiting long-term relief) associated with conventional pharmacotherapies (such as glucocorticoids, immunosuppressants and biological agents, among others), highlighting the holistic advantages of TCM.

Active pharmaceutical ingredients derived from TCM represent a key component of modern TCM research, serving not only as the pharmacodynamic material basis of compound formulations but also as candidates for drug development. According to data from China's National Medical Products Administration (194), a number of TCM formulations (such as Yinxieling granules, Xiaofeng Zhiyang granules and Fushu Zhiyang ointment), have entered the market, demonstrating efficacy in treating a number of pruritic disorders. Concurrently, the International Traditional Medicine Clinical Trial Registry (195), highlights three primary trends in TCM anti-pruritic clinical research: i) An increased proportion of mechanism verification studies; ii) accelerated development of novel TCM-based drugs; and iii) a marked rise in multicenter trials. Numerous clinical trials are currently being conducted, including a randomized, open-label, dose-finding, positive drug-controlled clinical trial evaluating the efficacy and safety of Jingfang mixture (ITMCTR2025000520) for chronic urticaria, a randomized, double-blind, placebo-controlled trial assessing Hefu Zhiyang lotion (ITMCTR2024000637) for chronic eczema, and a study investigating the regulation of antimicrobial peptides and Staphylococcus aureus colonization in AD by Guben Huashi formula (ITMCTR2025001890). These efforts reflect the growing integration of TCM with evidence-based methodologies to advance pruritus management.

TCM has been used to treat skin itching for a long time (180,181). Li et al (196) performed a systematic analysis of classical TCM prescriptions for itch management using association rule mining with the classical Apriori algorithm, as well as entropy clustering techniques to handle complex system features and unsupervised hierarchical clustering for autonomous stratification. The findings revealed that anti-inflammatory and immunomodulatory herbs dominate anti-pruritic TCM formulations, with the top five most frequently prescribed herbs being Rehmannia glutinosa (fresh Rehmannia root), Paeonia lactiflora (red peony root), Glycyrrhiza glabra (licorice root), Lonicera japonica (honeysuckle flower) and Forsythia suspensa (Forsythia fruit). Research has revealed that these herbs exert synergistic therapeutic effects through anti-inflammatory and immunomodulatory pathways (196). Core active substances, such as Rehmannia polysaccharides and catalpol from Rehmannia glutinosa (197–199), paeoniflorin from Paeonia lactiflora (200–203) and liquiritigenin A from Glycyrrhiza glabra (204–206), employ numerous regulatory mechanisms to target pruritus-related signaling pathways and inflammatory mediators. These findings not only support the scientific basis of ancient TCM prescription principles (207), but also provide a foundation for current pharmacological interpretation of their mechanisms (208,209). The present review aims to lay the groundwork for an improved understanding of the systemic regulatory networks of TCM compound formulations in pruritus treatment. Based on these findings, the present review continues to highlight current research regarding TCM treatments for cutaneous itch.

Rehmannia glutinosa, a perennial herbaceous plant from the Scrophulariaceae family. Its main bioactive components, Rehmannia polysaccharides and catalpol, exhibit specific molecular targeting of TLR4-mediated chronic pruritus mechanisms (197). Catalpol inhibits lipopolysaccharide (LPS)-induced production of TNF-α, IL-1β, IL-6 and prostaglandin E2 in RAW264.7 macrophages through blocking of the NF-κB and MAPK signaling pathways (198). Rehmannia polysaccharides reduce LPS-induced IL-6 and TGF-β production in macrophages by inhibiting the activation of the AKT/ERK/JNK pathway (199). These effects further block the TLR4-activated MyD88/IRAK/TRAF6-IKK-NF-κB/MAPK signaling pathway, reducing pro-inflammatory cytokine production and inflammatory cascades (210). This mechanistic data may establish a molecular basis for the use of Rehmannia glutinosa to treat pruritus caused by inflammatory skin diseases such as AD and psoriasis.

Paeonia lactiflora, the dried root of Paeonia lactiflora of the Ranunculaceae family. Paeoniflorin, its main bioactive component, exhibits marked therapeutic effects in inflammatory skin conditions such as psoriasis and allergic dermatitis (200,201). Paeoniflorin specifically targets the TSLP-mediated pruritic pathway, suppressing abnormal upregulation of TSLP and reversing IL-10 downregulation. By regulating the TSLP/IL-10 axis (202,203), paeoniflorin efficiently inhibits TSLP-activated JAK/STAT signaling-driven inflammatory cascades and itch signal transmission. These findings provide molecular evidence that Paeonia lactiflora may help alleviate pruritus caused by inflammatory skin diseases such as AD and psoriasis.

Glycyrrhiza uralensis, the dried roots and rhizomes of Glycyrrhiza uralensis, Glycyrrhiza glabra or Glycyrrhiza inflata from the Fabaceae family. Its main bioactive component, licochalcone A (LCA), exhibits therapeutic effects by precisely targeting TRPV1-mediated neurogenic pruritus processes. LCA inhibits TRPV1 channel activation and CGRP production, thus lowering neuronal hyperexcitability (204). LCA suppresses phosphorylation of the JAK1/STAT3 proteins (205), leading to decreased expression of pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β. These effects efficiently inhibit TRPV1-activated itch signal transduction and inflammatory cascades, establishing a potential molecular basis for Glycyrrhiza uralensis in the treatment of pruritus associated with inflammatory skin diseases such as AD and allergic dermatitis (206).

Lonicera japonica, the dried flower buds or newly opened blossoms of Lonicera japonica (Thunb.) from the Caprifoliaceae family. Its main bioactive component, Lonicera japonica polysaccharide-2 (LJP-2), exhibits therapeutic effects by precisely targeting TLR4-mediated chronic pruritus pathways. LJP-2 binds to the extracellular domain of TLR4 and inhibits MyD88 dimerization as well as NF-κB nuclear translocation (211). This reduces the activity of the NF-κB/MAPK signaling pathway, leading to decreased expression of pro-inflammatory cytokines such as TNF-α and IL-6. Concurrently, LJP-2 triggers the p62/nuclear factor erythroid 2-related factor 2 pathway (212), which promotes NLR family pyrin domain containing 3 inflammasome breakdown. These effects efficiently inhibit TLR4-activated inflammatory cascades and itch signal transduction, suggesting that Lonicera japonica may alleviate pruritus associated with inflammatory skin diseases, including AD (213).

Forsythia suspensa, a dried fruit from the Oleaceae family. Its main bioactive component, Forsythia ester glycoside B, exhibits therapeutic effects by precisely targeting TRPV3-mediated pruritic processes. This chemical particularly inhibits aberrant TRPV3 channel activity (214), which includes mutations and carvacrol activation. In a carvacrol-activated TRPV3 mutant (G573S) model, forsythia ester glycoside B increased 293 cell survival and lowered scratching behavior triggered by chemical stimuli in dry skin (214). These effects efficiently inhibited TRPV3 aberrant activation-induced itch signaling and inflammatory cascades. This mechanistic evidence establishes a molecular basis for the potential efficacy of Forsythia suspensa in treating acute and chronic pruritus, skin allergies and inflammatory dermatological diseases.

Overall, the aforementioned five classical active components of TCM have similar modes of action in the treatment of pruritus. These drugs target specific molecular nodes in pruritus pathways, such as TLR4, TSLP, TRPV1 and TRPV3, reducing downstream inflammatory signaling cascades such as NF-κB/MAPK, JAK/STAT and JAK1/STAT3 (215). This multi-target regulation decreases pro-inflammatory cytokines (including TNF-α, IL-6 and IL-1β) and modulates anti-inflammatory mediators (including IL-10) (216), thereby inhibiting inflammatory amplification and pruritic signal transmission. These findings establish the molecular basis for TCM's synergistic multi-target regulation of pruritus in inflammatory skin disorders such as atopic dermatitis (AD) and psoriasis, demonstrating its therapeutic advantage through a multi-component, multi-target, and multi-pathway approach.

Studies have indicated that active constituents from additional medicinal herbs, including Saposhnikoviae Radix (217–219), Dictamni Cortex (28,220), Moutan Cortex (221–223), Scutellariae Radix (224–227), Sophorae flavescentis Radix (228–230), Cicadae Periostracum (231), Cnidii Fructus (232–235), Thymi Herba (236,237), Sophorae tonkinensis Radix (238–240), Kochiae Fructus (241–243), Gentianae Radix (244–246), Tripterygii Radix (247,248), Arnebiae Radix (249,250), Tetradium ruticarpum (251,252) and Artemisia annua (253,254), also exhibit notable therapeutic value in ameliorating cutaneous pruritus (Table V).

Chinese herbal formulae, as the primary interventional technique within the diagnostic and therapeutic systems of TCM (255), achieve total organism management by combining the actions of diverse elements (256). Combinatorial approaches used in multi-herb formulations are key in the dynamic principles of pattern discrimination and treatment (257). Si and Zhao (258) used bibliometric methods to systematically analyze the composition principles of pruritus-related formulae, identify core compatibility frameworks using frequency statistics and herb cluster analysis, and conduct a focused quantitative investigation of the distribution patterns and cluster associations of high-frequency drugs. The findings showed that traditional formulae such as Longdan Xiegan Tang (gentian liver-draining decoction), Danggui Yinzi (angelica decoction), Xiaofeng San (wind-dispersing powder), Dihuang Yinzi (Rehmannia decoction) and Liuwei Dihuang Tang (six-ingredient Rehmannia decoction) exhibited marked therapeutic benefits in the treatment of cutaneous pruritus. Their mechanisms of action are based on a mix of holistic pattern discrimination and modern medical technology, as well as the multitarget regulatory qualities of chemical formulations (259). Furthermore, modern modified formulae and refined classical prescriptions have shown clear therapeutic value in both mechanistic research and clinical practice (260–262) by precisely optimizing herbal compatibility ratios, demonstrating the systemic benefits of compound formulations in regulating complex pathological networks.

Longdan Xiegan decoction, derived from the classical medical compendium Yi Fang Ji Jie (263), comprises 10 herbal components: Gentiana scabra (Longdancao), Scutellaria baicalensis (Huangqin), Gardenia jasminoides (Zhizi), Alisma plantago-aquatica (Zexie), Plantago asiatica (Cheqianzi), Angelica sinensis (Danggui), Rehmannia glutinosa (Dihuang), Bupleurum chinense (Chaihu), Paeonia suffruticosa (Mudanpi) and Prunella vulgaris (Xiakucao). The decoction significantly reduces ear swelling and skin pathology scores in eczematous rats while improving eczematological symptoms such as erythema, papules, and vesicles. These effects suggest its capacity to inhibit H1R/TRPV1 and PAR-2/TRPV1 pathways, downregulate pruritic-related proteins (e.g., IL-31, TSLP), suppress p38MAPK phosphorylation, and reduce the activity of inflammatory signaling pathways such as NF-κB, thereby attenuating epidermal thickening, hyperkeratosis, and dermal edema (264).

Danggui Yinzi, originating from the Song dynasty medical text Chong Ding Yan Shi Ji Sheng Fang (265), consists of 10 herbal ingredients: Angelica sinensis (Danggui), Paeonia lactiflora (Bai Shao), Ligusticum chuanxiong (Chuan Xiong), Rehmannia glutinosa (Sheng Di Huang), Schizonepeta tenuifolia (Jing Jie Sui), Saposhnikovia divaricata (Fang Feng), Tribulus terrestris (Bai Ji Li), Polygonum multiflorum (He Shou Wu), Astragalus membranaceus (Huang Qi) and Glycyrrhiza uralensis (Gan Cao). This formulation effectively targets the IL-33/ST2-mediated pruritic signaling pathway (266,267), inhibiting mast cell activation and degranulation. It also reduces the expression of mast cell tryptase and the release of pro-inflammatory cytokines such as TNF-α and IL-1β (266). Furthermore, it corrects the Th1/Th2 immunological imbalance by upregulating IFN-γ, downregulating IL-4 and IgE, as well as decreasing the production of leukotrienes (LTs; including LTB4 and LTC4) and their receptors [cysteinyl (Cys)-lekotriene receptor 1 (LTR1) and CysLTR2] (267). These effects notably disrupt the IL-33-induced neuroimmune-epidermal crosstalk network, reducing inflammatory amplification loops and easing pathological alterations such as dermal edema, capillary dilatation and epidermal barrier failure. The molecular pharmacological profile of Danggui Yinzi provides a mechanistic basis for its therapeutic efficacy in chronic pruritic skin diseases such as urticaria, which is associated with the IL-33-driven Th2-type pruritic pathway.

Xiao Feng San, derived from the Ming Dynasty medical text Wai Ke Zheng Zong authored by Chen Shigong, is among the most widely applied traditional Chinese medicine formulas in dermatological clinical practice. It comprises 13 herbal ingredients: Angelica sinensis (Danggui), Rehmannia glutinosa (Sheng Di Huang), Saposhnikovia divaricata (Fang Feng), Cicadae periostracum (Chan Tui), Anemarrhena asphodeloides (Zhi Mu), Gypsum fibrosum (Shi Gao), Sophora flavescens (Ku Shen), Akebia quinata (Mu Tong), Schizonepeta tenuifolia (Jing Jie), Arctium lappa (Niu Bang Zi), Atractylodes lancea (Cang Zhu), Sesamum indicum (Hu Ma), and Glycyrrhiza uralensis (Gan Cao). This formulation exerts anti-pruritic effects by precisely targeting IL-31/oncostatin-M receptor-β (OSMRβ)- and IL-33/ST2-mediated Th2-type chronic pruritus mechanisms (268). It markedly reduces serum levels of IL-31, IL-33 and IgE, and suppresses IL-17 release (269). Furthermore, it upregulates aquaporin-3 expression to restore epidermal barrier integrity (270). These actions effectively block the activation of the JAK/STAT, MAPK and NF-κB signaling pathways triggered by IL-31 and IL-33 (133,271–273), thereby inhibiting keratinocyte inflammation, mast cell degranulation and the neuroimmune-epidermal crosstalk-driven pruritic amplification cycle (16). This mechanistic framework provides a molecular basis for Xiaofeng San's therapeutic efficacy in treating Th2-dominated chronic pruritic disorders such as AD, directly aligning with the pathogenic role of IL-31/IL-33-activated neuroimmune-inflammatory networks.

These three TCM formulations contribute to curing Th2-type pruritus by targeting key cytokine pathways, including the TSLP/TSLPR/IL-7Rα, IL-31/OSMRβ and IL-33/ST2 signaling axes (133,271). This multi-target approach disrupts the inflammatory amplification cycle in the ‘neuro-immuno-epidermal’ crosstalk network and inhibits key signaling pathways, including the JAK/STAT, MAPK and NF-κB signaling pathways (272,273). As a result, these formulations demonstrate a coordinated reduction in mast cell activation, keratinocyte dysfunction and skin barrier deterioration (16). These findings provide the groundwork for multi-target synergistic intervention in Th2-driven chronic pruritic dermatoses such as AD and urticaria, determining the TCM therapeutic premise of systemic control through multi-pathway synergy.

In addition to the aforementioned Chinese herbal formulae, other compound prescriptions such as Guizhi Mahuang Ge Ban Tang (274) (cinnamon and Ephedra half-and-half decoction), Taohong Siwu Tang (275) (peach kernel and Carthamus four-substance decoction), Huanglian Jiedu Tang (276,277) (Coptis toxin-resolving decoction), Jiawei Guomin Jian (278–281) (modified allergy-relieving decoction), Danggui Kushen Wan (282,283) (Angelica and Sophora pill), Jiuwei Yong'an Granule (284) (nine-ingredient Yong'an granule) and Yupingfeng San (285,286) (jade wind-barrier powder) have also been demonstrated to alleviate cutaneous pruritus (Table VI).