Pruritus is a warning abnormal sensation elicited by
stimuli that frequently results in intense scratching impulses that
markedly impair the sleep, mood and quality of life of patients
(1), as well as potentially
causing skin damage, secondary infections or even life-threatening
complications (2–4), making it a key public health issue.
Pruritus has a complex etiology, with clinical classification
typically divided into four categories (5–7): i)
Cutaneous (derived from skin diseases such as allergic,
inflammatory or infectious conditions, as well as insect bites);
ii) systemic (extracutaneous diseases such as hepatic, renal,
hematological or drug-related disorders); iii) neuropathic
(secondary to neurological diseases); and iv) psychogenic
(conditions directly triggered by psychosocial factors are closely
associated with neuropsychiatric disorders, such as anxiety
disorders, depressive disorders and somatic symptom disorders).
These categories frequently coexist, resulting in mixed pruritus,
which is more common [in the etiological classification of chronic
pruritus, mixed etiology (e.g., coexistence of inflammatory and
neuropathic factors) is a critical consideration] in clinical
practice (8). For example, elderly
individuals are more likely to develop mixed pruritus due to
factors such as decreased sebum secretion and natural degradation
of their skin barrier (9), as well
as multiple chronic comorbidities (systemic) and neurodegenerative
changes (neuropathic), making them a particularly high-risk group.
Furthermore, environmental factors such as pollution weaken the
skin barrier, raising the global risk of pruritus-related disorders
in ~3 billion individuals (10),
highlighting the complexity and urgency of prevention and
therapy.
A deeper understanding of pruritus processes is
therefore necessary for developing novel therapies. According to a
previous study (11), pruritogens
stimulate sensory nerve terminals through damaged epidermal
barriers or immune cell activation, stimulating a number of
receptors [examples include G protein-coupled receptors (GPCRs)
such as protease-activated receptors 1/2 (PAR-1/2), Mas-related G
protein-coupled receptor (MRGPR) subtypes (e.g., MRGPRD, MRGPRX1,
MRGPRX2), serotonin (5-HT) receptors including 5-HTR2B, and
cytokine receptors such as interleukin-31 receptor A (IL-31RA)
mediating IL-31 signaling, and IL-17 receptor A (IL-17RA) binding
IL-17A] and changing transient receptor potential (TRP) as well as
voltage-gated sodium (NaV) channels to generate action potentials.
These signals are subsequently transmitted to regions in the brain
such as the parabrachial nucleus (PBN) and amygdala through spinal
gastrin-releasing peptide receptor (GRPR) neurons, whereby
affective and motivational states are modulated, ultimately
resulting in the ‘pruritus-scratch’ cycle.
Currently, Western medicine treats symptoms
primarily with antihistamines, glucocorticoids and
immunomodulators, which exhibit short-term efficacy but are
associated with long-term risks, such as skin atrophy (12), pigmentation, increased infection
susceptibility (13) and relapse
after discontinuation, limiting long-term relief (14). Traditional Chinese medicine (TCM)
has been used in the treatment of pruritus for a long time, with
emphasis on syndrome differentiation and general regulation. TCM
therapy has shown a unique ability to alleviate symptoms, reduce
recurrence and improve quality of life (15) by integrating synergistic
multi-component, multi-target and multi-pathway effects of single
herbal active components and compound formulations (16). However, despite its promising
efficacy and safety, the precise mechanisms of TCM treatment and
the complex interactions between its components are unclear
(15,16), hindering the development and
practical application of novel TCM therapies. To address this, in
the present review, a novel mechanistic framework for pruritus that
includes the sequential phases of
‘initiation-transduction-amplification-central integration’ was
developed, methodically clarifying the pathogenic underpinnings.
Furthermore, the present review describes TCM intervention
strategies at the molecular level, demonstrating that active
compounds from single herbs and conventional compound formulations
work together to modulate pruritus signaling networks through
multi-target interactions. In addition, the present review explores
multidimensional and multilevel action pathways, as well as
advancements from single herbs to compound formulations,
effectively bridging the gap between the theoretical framework of
TCM and the modern pathophysiological mechanisms of pruritus,
unlike existing studies that focus on monolithic Western medical
perspectives (17) and related
guidelines emphasizing clinical workflows over mechanistic
explanations (18). The aim was
not only to deepen the systemic understanding of pruritus
pathogenesis but also to provide a robust theoretical foundation
for novel drug development, clinical precision translation and
innovative integrative TCM-Western medicine therapeutic
strategies.
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.
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).
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).
TRP superfamily ion channels serve as key components
in the regulatory network that coordinates the dynamic balance
between neuronal activation and epidermal barrier homeostasis in
the pathogenesis of cutaneous pruritus (83,84)
(Fig. 3). The TRP superfamily ion
channels are key downstream effectors of GPCRs and PARs (11,83).
The capsaicin receptor TRPV1 can detect high
temperatures (>42°C), low pH (<5.9) and capsaicin. It is
widely distributed throughout the skin and aids in the maintenance
of the epidermal barrier, activating sensory neurons by binding to
histamine receptors. PAR2 and PAR4 mediate non-histaminergic
pruritus and contribute to chronic neuroinflammation by sensitizing
TRPV1, thereby promoting pruritic responses (85).
Conversely, TRPA1 is a receptor for pain and itch,
triggered by cold temperatures (<17°C), menthol or
cinnamaldehyde. TRPA1 activity is regulated positively by numerous
pruritus-associated GPCRs (86).
TRPA1-knockout mice display markedly reduced acute scratching
reactions to CQ, adrenomedullin and sphingosine-1-phosphate
(87,88), as well as reduced scratching
activity in chronic dry skin-induced itch paradigms (89).
Loss-of-function mutations in TRPV3 impair PAR2
activity in keratinocytes and reduce neuronal activation (90,91).
By contrast, gain-of-function variants of TRPV3 are associated with
AD and Olmsted syndrome, with pharmacological inhibition of TRPV3
alleviating atopic itch (85,92).
Further studies have shown that IL-31 enhances TRPV3 expression in
keratinocytes through the natriuretic peptide receptor (NPR)-1
receptor in a brain natriuretic peptide (BNP)-dependent manner
(IL-31 stimulates sensory neurons to release BNP, which then
upregulates NPR1-mediated TRPV3 expression). This cascade promotes
the release of serine protease E1 and facilitates itch signaling
(93,94).
TRP melastatin (TRPM)-8 is a cold-sensitive ion
channel that operates within the temperature range of 8–28°C
(96,97). TRPM8 can be triggered by
methoxypropanediol to reduce irritation and improve skin barrier
restoration. TRPM8 optogenetic activation inhibits SP release from
neurons in the spinal dorsal horn that express GRPR, disrupting the
itch-scratch cycle (98).
TRP canonical (TRPC)-3 and TRPC4 are extensively
expressed in primary sensory neurons and have been associated with
pro-inflammatory sensitization (99). Mice that lack TRPC3/C4 exhibit
markedly reduced scratching reactions to non-histaminergic
pruritogens (99). In a contact
hypersensitivity model, TRPC3 expression and function in the
trigeminal ganglia were both increased (99). TRPC3 inhibition, either
pharmacological or genetic, reduces spontaneous scratching
(99). Additional research has
revealed that genetic deletion of TRPC4 notably reduced itching
caused by the selective serotonin reuptake inhibitor medicine
sertraline (100,101).
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.
Spatiotemporal specificity of pruritic signaling is
controlled by the biogenic amine system through a network of
numerous receptor subtypes, including histamine and 5-HT (106). Histamine, a classical
pruritogenic mediator, is primarily stored in mast cells and
basophils, but keratinocytes produce trace amounts when disturbed
(107). Histamine produced
through IgE-Fc ε receptor I cross-linking or non-IgE mechanisms
(such as neuropeptides or thrombin) activates TRPV1/TRPA1 channels
through histamine receptor 1 (H1R)/H4R receptors (11), causing membrane depolarization
through the phospholipase C/12-lipoxygenase pathway. This
depolarization causes NaV1.7/NaV1.8-mediated action potentials in
the DRG, as well as neuropeptide release, resulting in neurogenic
inflammation and itching (11). In
animal models (108), combined
H1R/H4R blockade has been shown to reduce scratching more
effectively compared with single-target inhibition, indicating that
multi-receptor methods hold therapeutic promise. Furthermore, H4R
promotes Th2 cell IL-5/IL-13 secretion, which accelerates the
progression of AD (109),
suggesting that blocking H4R could be a novel therapeutic option
for AD.
5-HT regulates acute and chronic pruritus through a
number of mechanisms using unique peripheral receptor subtypes as
detailed in Table I (23,83,110–114), representing novel developments in
individualized chronic pruritus treatment: 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 (83).
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).
Spinal pruriceptive signaling requires a dynamic
balance between excitatory and inhibitory circuits. GRP-expressing
neurons in the spinal cord use GRP receptors to relay peripheral
itch signals (164,165). Peripheral nociceptive inputs
inhibit the GRP-GRPR pathway by activating basic helix-loop-helix
family member E22 interneurons, which reduces chemical itch.
Somatostatin increases pruritus through binding to somatostatin 2
receptors, inhibiting dynorphinergic neurons and disinhibiting
GRPR+ neurons (166,167).
In pruritus research, the labelled line theory
posits that peripheral pruriceptors, specific receptors/ion
channels, spinal interneurons, ascending projection pathways and
cortical neurons form a dedicated ‘labelled’ pathway responsible
for itch signal recognition, transmission and perception. This
pathway diverges from other sensory modalities like pain at
critical nodes, explaining phenomena such as scratching alleviating
itch while exacerbating pain. For instance, itch and pain share
certain mediators (e.g., IL-33, TRP channels) but exhibit
modality-specific differences: IL-31/periostin predominantly drive
pruritus, whereas CCL2/CXCL dominate pain; µ-opioid receptor
activation alleviates pain but worsens itch. These observations
support the concept of partially overlapping yet functionally
segregated pathways (156). The
theory also guides targeted therapies: Dupilumab targets
Th2-associated pruritus (171),
Nalfurafine acts on the GRPR pathway (157) and gabapentin addresses
neuropathic itch (8), all
reflecting the ‘pathway-specific treatment’ paradigm.
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.
TCM has evolved a complete pathological
understanding of pruritus throughout millennia of clinical practice
(180,181), establishing a systematic
etiological and mechanistic framework that is consistent with
modern medical perspectives. In TCM theory, pruritus is classified
into the syndromes of itch-wind (yang-feng) or wind-induced
pruritus (180), with its core
pathogenesis scientifically interpreted as follows: External
factors such as allergen exposure, parasitic infections or
humid-hot environments disrupt the skin barrier integrity (stratum
corneum dysfunction) and trigger localized inflammation (local
inflammatory response) (182,183), leading to microcirculatory
dysregulation and heightened neuronal excitability (184). Alternatively, prolonged skin
dryness (xerosis), nutritional inadequacies or reduced epidermal
barrier function (epidermal barrier impairment) cause keratinocyte
dehydration (185), immune cell
infiltration and secondary neurogenic inflammation (186), which results in persistent
pruritus. This theoretical approach emphasizes symptom-based
phenotypic categorization for individualized diagnosis, creating
the pathophysiological groundwork for precision medicine in
contemporary dermatology. These ideas are associated with the
etiology-driven classification systems provided by the
International Forum for the Study of Itch (11,187–189), which merge classical conceptions
with modern scientific paradigms.
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.
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.
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.
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).
The present review provides a systematic review of
the diversity and complexity of pruritus mechanisms, with a focus
on the multi-pathway inhibition of pruritic signaling by active
components of single Chinese herbs and compound formulations
through synergistic modulation of the ‘neuro-immune-cutaneous’
interaction network, specifically the following interventions: i)
Suppression of receptor activation (including PARs and MRGPRs) and
subsequent sensitization of downstream TRP channels; ii) inhibition
of cytokine-mediated Th2 immune bias (for example, IL-4, IL-13 and
IL-31) and mast cell degranulation; and iii) promotion of epidermal
barrier repair (particularly in compound formulations). These
findings provide notable mechanistic evidence to support TCM
multi-target and holistic therapeutic strategies for pruritus.
Herbal components work synergistically to regulate peripheral
signaling and central integration, making them safer compared with
single-target therapy for interrupting the
‘itch-scratch-inflammation’ cycle (287).
However, certain limitations remain. Firstly,
interactions between components within compound formulations are
not fully understood and the clinical applicability of existing
experimental models needs to be validated by larger-sample clinical
trials. Future studies should aim to explore novel
pruritus-associated signaling pathways, multi-target synergistic
therapies and combined Chinese-Western therapeutic techniques to
improve overall efficacy.
The following suggestions represent treatment
approaches combining TCM and Western medicine: Firstly, following
the TCM principles of therapeutic customization and symptom
distinction may improve clinical outcomes. Future research should
aim to build upon conventional approaches while actively
investigating novel interventions and technologies. For example,
modern biotechnology could be utilized to enhance herbal extraction
and formulation techniques, thereby creating next-generation herbal
preparations. Similarly, the integration of external TCM therapies
such as acupuncture, cupping and herbal bathing with contemporary
physical therapies should be considered. Secondly, further
collaboration between TCM and Western medical professionals is
necessary to capitalize on the advantages of the other. To maximize
holistic regulation, lower recurrence rates, increase treatment
efficacy and improve the quality of life of patients with chronic
diseases, standardized, evidence-based diagnostic and therapeutic
protocols must be established. These integrated methods seek to
ensure clinical rigor and translational relevance in current
healthcare systems by bridging the gap between established clinical
practices and evidence-based standards.
To ensure scientific rigor and the preservation of
TCM characteristics, randomized controlled trials (RCTs) combining
TCM and Western medicine should strictly adhere to randomization,
control and blinding principles (288,289) while fully integrating TCM's
syndrome differentiation framework into treatment protocols.
Specific strategies include core grouping criteria based on TCM
syndrome differentiation and using clear (290), standardized syndrome diagnostic
criteria as the primary stratification component, rather than
relying primarily on Western disease categories. Blinding
implementation requires developing placebos that are comparable in
appearance, flavor and taste to active herbal medicines, as well as
keeping outcome assessors blind to group allocation to increase
objectivity (291). To guarantee
acceptable statistical power, the sample size should be determined
using mixed-effects models for continuous variables (for example,
pruritus ratings) and χ2 tests for categorical outcomes
(292). Multicenter coordination
requires unifying inclusion/exclusion criteria, diagnostic
methodologies and treatment processes across centers, as well as
centralizing training and developing a robust quality control
system to improve sample representativeness and result
dependability (293). Outcome
metrics include clinical indicators, quality-of-life assessments
and TCM-specific syndrome scores, which may help capture treatment
outcomes properly (294). To
address common issues, standardized syndrome differentiation
training must be implemented to ensure diagnostic consistency
(295), thereby establishing
clear protocols for treatment frequency, procedural standardization
and adherence optimization (for example, rationalizing treatment
schedules and improving follow-up). These efforts seek to
standardize and modernize TCM RCTs, increasing their scientific
validity and reputation.
Emerging technologies present promising prospects
for mechanistic study and medication development. Structural
biology and multi-omics methods, such as cryo-electron microscopy
and single-cell sequencing, can identify molecular connections
between herbal components and pruritic targets. Artificial
intelligence and metabolomics can clarify the holistic effects,
compatibility principles and pharmacodynamic material basis of
compound formulations. International multicenter RCTs will
establish more evidence-based efficacy evaluation systems.
Exploring developing domains (such as skin microbiota and
epigenetics) may improve the understanding of TCM mechanisms in
controlling ‘neuro-immune-microecological’ cross-system
interactions.
These advancements present novel possibilities for
combining Chinese and Western medicine in pruritus therapy,
stressing the necessity of multi-target and systemic approaches.
TCM is well-positioned to provide more systematic and accurate
solutions for global pruritus regulation through interdisciplinary
collaboration and technological integration, as well as strong
scientific support for developing integrated diagnostic and
treatment paradigms.
The present study was supported by The Li Yongji National Master
Traditional Pharmacist Legacy Studio Initiative (grant no.
14061240013) and The Open Project of the State Key Laboratory for
Innovation and Integration of Classical Formulations and Modern
Chinese Medicine (grant no. LSLSKL20240403).
Not applicable.
HZ wrote, reviewed and edited the original draft.
HZ was also responsible for conceptualization, conducting the
investigation and contributing towards the resources used. YoL
conducted project administration, provided supervision and
contributed towards the resources used, and writing, reviewing and
editing of the manuscript. YuL conceptualized the present study,
curated the data, conducted the investigation, and wrote, reviewed
and edited the manuscript. DF, LZ and RC conceptualized the study,
and contributed towards conducting the investigation, the resources
used, and writing, reviewing and editing of the manuscript. XZ and
JD acquired the funding and contributed towards conceptualizing the
present study, conducting the investigation, the resources used,
and writing, reviewing and editing of the manuscript. Data
authentication is not applicable. All authors have read and
approved the final version of the manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
During the preparation of this work, artificial
intelligence tools (Grammarly) were used to improve the readability
and language of the manuscript or to generate images, and
subsequently, the authors revised and edited the content produced
by the artificial intelligence tools as necessary, taking full
responsibility for the ultimate content of the present
manuscript.
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