The global cancer burden has reached alarming
proportions, with the International Agency for Research on Cancer
(IARC) reporting >20 million new cases and 9.7 million
fatalities in 2022, a figure projected to surge to 35 million by
2050, creating an urgent need for innovative therapies that balance
efficacy with safety (1). This
escalating crisis has renewed interest in Traditional Chinese
Medicine (TCM) as a source of complementary agents to counter the
limitations of conventional treatments, such as toxicity and
resistance (2,3), with Schisandra chinensis (Wu
Wei Zi) emerging as a pivotal candidate. Its berries, called 'five
flavors' (sour, sweet, bitter, pungent, and salty), are classified
in the Chinese Pharmacopoeia (2020) as warm and sour-sweet
(5), targeting lung/heart/kidney
meridians for chronic cough and liver disorders (4-6).
Critically, modern research has validated its systemic
bioactivities: organ protection via Nrf2/NF-κB modulation to
alleviate oxidative stress and inflammation (7,8),
neuro-hepatic shielding through antifibrotic repair (9-11), and immune reprogramming via
macrophage/Th1-Th2 regulation (12,13) (Fig. 1).
Among its bioactive lignans, Wuweizisu B
(Schisandrin B, WSB) stands out as the premier anticancer agent
(6,14-17) (Fig. 2), boasting exceptional
bioavailability and tissue distribution (14,18) to orchestrate pleiotropic effects
from hepatoprotection to proliferation control (19-22). Its structural analogs (such as
schisandrin A/C and gomisins) synergistically combat cancer through
direct tumor suppression (apoptosis/cell cycle arrest), metastasis
blockade, microenvironment remodeling (immune activation), and
chemosensitization (MDR reversal via STAT3/P-gp/survivin
modulation) (4,17,23-27). Notably, WSB's ability to reverse
MDR, a major driver of chemotherapy failure, positions it as a key
ally against refractory cancers (28-30).
The present review therefore deciphered WSB's
anticancer potential through molecular mechanisms, organ-specific
efficacy, and clinical translation strategies as a dual
chemosensitizer-cytoprotective agent, bridging traditional wisdom
with contemporary pharmacology to chart a roadmap for integrated
oncology (Figs. 3-6).
As a prototypical multitarget natural compound, WSB
exhibits remarkable therapeutic potential across a spectrum of
gastrointestinal malignancies through its unique ability to
simultaneously modulate oncogenic signaling networks, metabolic
reprogramming, and tumor microenvironment remodeling. This section
systematically elucidates the organ-specific anticancer mechanisms
of WSB along the digestive tract, supported by compelling
preclinical evidence highlighting it as a promising candidate for
integrative oncology approaches (Fig. 3).
GC remains a significant global health burden, with
the IARC reporting ~968,000 new cases and 660,000 deaths worldwide
in 2022, ranking fifth in incidence and mortality among all cancers
(1,31). Chemotherapy and immunotherapy,
have spurred interest in TCM as a complementary approach for GC
treatment (32). WSB exhibits
potent antitumor effects in GC. WSB exerts its antitumor effects
through a coordinated molecular cascade: by effectively inhibiting
STAT3 phosphorylation, WSB inactivates this oncogenic transcription
factor, thereby blocking downstream survival genes (Bcl-2 and
Survivin) and metastatic drivers (33) (Fig. 3; Table I). Crucially, suppression of
STAT3 expression directly represses Cyclin D1 transcription
(34) (Fig. 3), leading to significant
downregulation of the expression of Cyclin D1 mRNA, the core
regulator of the G1/S transition, which induces cell
cycle arrest at the G0/G1 phase in SGC-7901
cells. Notably, the optimal inhibitory effect was observed at a
concentration of 50 mg/l after 48 h of treatment (35) (Fig. 3; Table I). However, this therapeutic
cascade is concentration dependent: while 50 mg/l optimally
balanced these effects, higher doses (100 mg/l) paradoxically
activated protective autophagy via reactive oxygen species
(ROS)/NF-κB feedback, potentially compromising treatment efficacy
(36) (Fig. 3).
Despite these advances, the precise molecular
mechanisms underlying the anti-GC effects of WSB remain unclear.
Furthermore, studies indicate that the effective in vitro
concentration of WSB (50 mg/l) far exceeds the achievable peak
plasma concentration in humans (2.1 μM) (37). Existing research is based solely
on cell and mouse experiments and lacks tumor microenvironment
simulation, which may lead to overestimation of clinical efficacy.
Future studies should focus on elucidating these pathways to
facilitate the clinical translation of WSB-based therapies.
CRC ranks as the third most prevalent malignancy
globally, with GLOBOCAN 2022 reporting 1.9 million new cases and
930,000 mortalities annually (38). Projections indicate that this
burden will increase to 3.2 million cases by 2040, underscoring the
urgent need for safer therapies. While current regimens combining
5-Fluorouracil (5-FU)-based chemotherapy with surgery/radiotherapy
remain standard, ≥50% of patients experience grade 3-4 toxicity,
including myelosuppression, gastrointestinal injury, and
neurotoxicity (39,40). These limitations highlight the
imperative for novel agents such as WSB that synergize with
conventional therapies while mitigating adverse effects.
Critically, TGF-β drives metastatic plasticity by
dynamically regulating both EMT and its reverse process,
mesenchymal-epithelial transition (MET). TGF-β induces EMT through
the activation of the suppressor of mothers against decapentaplegic
(SMAD) and non-SMAD pathways, leading to the suppression of
epithelial genes (such as CDH1) and the upregulation of mesenchymal
markers (such as VIM and FN1), thereby enabling cancer cell
migration and invasion (45,48) (Fig. 3). Conversely, at metastatic
sites, reduced TGF-β signaling promotes MET through SMAD7-mediated
suppression of the EMT transcription factors SNAIL/ZEB and
reactivation of the miR-200 family, which collectively restore
epithelial phenotypes to facilitate metastatic colonization
(49,50) (Fig. 3). This bidirectional regulation
of cellular plasticity highlights the central role of TGF-β in
coordinating both the dissemination and secondary outgrowth of
metastatic cancer cells.
Similar to its mechanism in colorectal cancer, WSB
also exhibits inhibitory effects on TGF-β-induced EMT in lung
cancer (LC) and breast cancer (BC). In LC, the WSB downregulates
the expression of proteins such as TGF-β1 and Bcl-2 while
upregulating p53 and p21 expression (51) (Fig. 3; Table I). These regulatory effects
reduce the suppression of epithelial genes and the upregulation of
mesenchymal markers. In BC, WSB blocks TGF-β-promoted ROS
production and increases cell motility by inhibiting NADPH oxidase
4, thereby reducing the metastasis of BC cells (52) (Fig. 3). Collectively, these findings
underscore WSB's conserved capacity to target the TGF-β-mediated
EMT across diverse malignancies, with context-dependent molecular
nuances tailored to tissue-specific pathways. Such cross-organ
inhibitory activity reinforces the WSB as a promising candidate for
developing broad-spectrum antimetastatic therapeutics, in cancers
characterized by dysregulated TGF-β-EMT signaling axes.
In colitis-associated cancer models, WSB
demonstrates dual chemopreventive effects: FAK-dependent tight
junction stabilization (increased ZO-1 expression) and microbiota
remodeling (increased Lactobacillus abundance with reduced
Escherichia coli colonization), reducing tumor multiplicity
by 75% (53) (Fig. 3; Table I). Additionally, compared with
that in the general population, the incidence of colitis-associated
cancer (CAC) induced by ulcerative colitis (UC) is markedly greater
(54,55). Moreover, the pathogenesis of UC
is closely associated with environmental factors, genetic
predisposition, the gut microbiota, and immune dysregulation
(56,57). WSB markedly inhibits the
differentiation of the proinflammatory Th17 cells and IL-17
secretion while promoting the generation of immunosuppressive Treg
cells, thereby preventing CAC development and maintaining
intestinal immune homeostasis (21) (Fig. 3).
Building upon the multitarget mechanism of WSB in
coordinately regulating the microbiota-barrier-immunity axis,
through the FAK-dependent tight junction restoration and the
microbiota remodeling to suppress the carcinogenic microenvironment
coupled with immune reprogramming to block the inflammation-cancer
transition from UC to CRC, its integrated preventive and
therapeutic potential offers novel strategies for high-risk UC
patients. Although preclinical data are promising, clinical
translation of WSB still faces challenges in terms of
pharmacokinetic optimization and validation of target biomarkers
such as SIRT1/SMURF2. Current exploratory trials are focusing on
combination therapies of WSB with immune checkpoint inhibitors (TCM
+ immunotherapy), which may overcome chemoresistance through
synergistic effects and unlock new therapeutic dimensions for
high-risk CAC patients. Furthermore, integration with targeted
delivery systems could enhance its translational value, enabling
the transition from the multi-mechanism intervention to precision
medicine (58).
Nonalcoholic fatty liver disease (NAFLD) has emerged
as a significant global health challenge, affecting 25-30% of
adults worldwide; the progressive of NAFLD, nonalcoholic
steatohepatitis, occurs in 10-20% of cases and often progresses to
cirrhosis and HCC (59-61). In the absence of FDA-approved
therapies for NAFLD/nonalcoholic steatohepatitis, WSB, a bioactive
lignan derived from Schisandra chinensis, has shown promise
as a multi-target therapeutic agent capable of modulating metabolic
homeostasis, inflammatory responses, and fibrotic processes.
Mechanistically, WSB ameliorates hepatic steatosis by activating
the AMPK/mechanistic target of mTOR pathway, which enhances
autophagic flux, promotes fatty acid oxidation, and suppresses de
novo lipogenesis (62-64) (Fig. 4).
Notably, hepatic steatosis is often the initial step
in NAFLD progression, and unresolved steatosis can drive the
development of liver fibrosis, a critical pathological feature that
accelerates disease severity. Liver fibrosis is primarily driven by
the activation of hepatic stellate cells (HSCs), and WSB targets
these activated HSCs through multiple coordinated pathways to exert
anti-fibrotic effects. It induces mitochondrial-dependent apoptosis
in HSCs by modulating the Bax/Bcl-2 ratio and activating caspase-3,
while simultaneously inhibiting TGF-β1-induced HSC activation
(65) (Fig. 4). WSB promotes ferroptosis in
HSCs via NCOA4-mediated ferritinophagy, suggesting a novel approach
for fibrosis treatment (66)
(Fig. 4). Cannabinoid receptor 2
has been identified as a key target in liver fibrosis, and WSB
alleviates CCl4-induced fibrosis by inhibiting the NF-κB
and p38 mitogen-activated protein kinase (MAPK) signaling pathways
in Kupffer cells, thereby reducing inflammatory cytokine release
(67-69) (Fig. 4). Further studies revealed that
WSB directly targets miR-101-5p, downregulating the activity of the
TGF-β signaling pathway to inhibit fibrosis (70-72) (Fig. 4).
As well as targeting HSCs and Kupffer cells, WSB
modulates macrophage polarization to further alleviate liver
inflammation and fibrosis, although this regulation is context- and
dose-dependent, reflecting its adaptability to diverse
microenvironments. WSB inhibits peroxisome proliferator-activated
receptor γ (PPARγ)-mediated NF-κB activation to suppress M1
macrophage markers (CD86/TNF-α) in liver fibrosis models (73) (Fig. 4), under oxidative stress, it
promotes M2 polarization via the Nrf2 pathway (74) (Fig. 4), while in tumor
microenvironments, high-dose WSB may increase immunosuppression
through STAT3 (75) (Fig. 4). These seemingly contradictory
results probably reflect the WSB's multitarget regulatory effects
on macrophage plasticity rather than genuine mechanistic
conflicts.
Moreover, the therapeutic potential of WSB in liver
disease extends to regenerative strategies: It enhances the
differentiation of human umbilical cord mesenchymal stem cells into
functional hepatocyte-like cells by activating the JAK2/STAT3
pathway, which could complement its antifibrotic effects by
promoting liver repair (76)
(Fig. 4). However, compared with
those of other differentiation methods, the efficiency and
functional maturity of WSB-induced HLCs require thorough
assessment. More importantly, the direct application of WSB in
vivo to modulate the fate of the endogenous or the transplanted
MSCs requires a careful evaluation of pharmacokinetics, targeted
delivery, potential off-target effects on other cell types, and
long-term safety.
As NAFLD progresses to advanced stages, cirrhosis
can predispose patients to HCC, a leading cause of cancer-related
mortality globally, with limited therapeutic options for
advanced-stage patients (77).
WSB demonstrates significant anti-HCC activity through mechanisms
that align with its earlier roles in metabolic regulation and
inflammation while also targeting tumor-specific pathways. It
synergizes with NK cells to induce pyroptosis in HepG2 cells via
perforin-granzyme B-caspase 3-GSDME, highlighting its role in
immune microenvironment modulation (24) (Fig. 4; Table I). The Ras homolog family member
α/ρ-associated protein kinase 1 (RhoA/ROCK1) pathway, which is
involved in HCC cell proliferation and metastasis, is effectively
suppressed by WSB, leading to inhibited migration and invasion of
Huh-7 cells both in vitro and in vivo (78-80) (Fig. 4; Table I). These findings underscore the
potential of WSB as a multifaceted therapeutic agent for treating
HCC that targets both tumor cells and the immune system. However,
the narrow therapeutic window (IC50 ~266.4 μM in
HepG2 cells vs. significant toxicity in normal cells at >200
μM) poses a major translational challenge (81). In addition, achieving effective
antitumor concentrations in vivo without unacceptable
toxicity may require advanced delivery strategies or synergistic
combinations with standard therapies.
In summary, while WSB shows preclinical promise for
NAFLD, fibrosis, and HCC via multiple target mechanisms, its
translational challenges are significant. The narrow therapeutic
window and context-dependent immune modulation complicate clinical
application. Key gaps include defining the in vivo
therapeutic window, developing toxicity mitigation strategies (such
as targeted delivery), and obtaining human pharmacokinetic/safety
data, necessitating rigorous clinical trials.
CCA, a highly aggressive malignancy originating from
the biliary epithelium with frequent extension to the ampulla of
Vater (82), represents the
second most common primary liver cancer and remains notoriously
resistant to conventional chemotherapy, contributing to its dismal
5-year survival rate, which is <20% for advanced cases (83). Preclinical studies have
demonstrated that WSB exerts multimodal anti-CCA activity through
i) potent induction of mitochondrial apoptosis, as evidenced by an
increased Bax/Bcl-2 ratio and significant activation of caspase-3/9
and PARP cleavage and ii) effective G0/G1
cell cycle arrest via downregulation of Cyclin D1 and CDK4/6
inhibition at clinically achievable concentrations (84) (Fig. 3; Table I). These findings demonstrate the
potential of WSB as a promising therapeutic candidate, particularly
given its dual-targeting ability against both proliferative
signaling and apoptotic resistance pathways, two hallmark features
of CCA pathogenesis that contribute to clinical
chemoresistance.
GBC, one of the most aggressive malignancies of the
biliary system, is associated with a dismal clinical prognosis.
Studies by Pehlivanoglu et al (85) have indicated that only 5% of
invasive GBC patients are diagnosed at the early T1b stage, with a
5-year survival rate of up to 92%; however, most patients are
diagnosed at the locally advanced or metastatic stage, resulting in
an overall 5-year survival rate of <10%. Furthermore, Brindley
et al (86) reported that
the objective response rate to current chemotherapy regimens (such
as gemcitabine plus cisplatin) for biliary tract cancers, including
GBC, is only ~20%, highlighting the urgency to explore novel
therapeutic agents (86)
(Table I). As an active
component derived from the traditional Chinese herb, WSB has
recently demonstrated multitargeted antitumor potential in GBC
treatment, with its mechanisms of action supported by multiple
studies (84,87,88). In terms of apoptosis induction,
Yang et al (84) reported
that WSB can upregulate the proapoptotic protein Bax and
downregulate the antiapoptotic protein Bcl-2, disrupt mitochondrial
membrane potential, promote the release of cytochrome c,
activate the caspase-9/3 cascade, and cleave PARP, thereby inducing
apoptosis in cholangiocarcinoma cells (Fig. 3; Table I). Similarly, studies on BC have
confirmed that WSB can enhance mitochondrial apoptotic signaling
through a ROS-mediated endoplasmic reticulum stress pathway (such
as upregulating CHOP and GPR78), suggesting a common mechanism of
apoptotic regulation across different tumor types (52) (Fig. 3). With respect to cell cycle
regulation, Hui et al (87) reported that the overexpression of
Cyclin D1 in GBC is closely associated with poor prognosis. WSB can
markedly inhibit the activity of the Cyclin D1/CDK4/6 complex while
upregulating the expression of the CDK inhibitor p21, thereby
blocking the phosphorylation of the retinoblastoma protein (Rb) and
causing cell arrest in the G0/G1 phase
(Fig. 3; Table I). This mechanism is highly
consistent with the action pathway of CDK4/6 inhibitors observed in
BC, further validating its rationality (88) (Table I).
Notably, the antitumor potential of WSB is not
limited to GBC. Studies on its mechanisms in various other tumors,
such as BC, have shown commonalities in regulating apoptosis, the
cell cycle, and metastasis, providing a basis for its potential as
a broad-spectrum antitumor candidate. In terms of clinical
translation, combined with the current application of targeted
drugs such as FGFR and IDH1 inhibitors in biliary tract cancers
(89), WSB is expected to be
used in combination with existing targeted immunotherapies, further
enhancing the therapeutic efficacy of GBC through synergistic
effects on multiple pathways (90,91).
NPC represents a distinct epithelial malignancy with
a unique geographical distribution and strong etiological
association with EBV infection (92). While radiotherapy demonstrates
excellent efficacy in early-stage disease (achieving 90% cure
rates), the majority of patients present with locally advanced or
metastatic disease at diagnosis because of the tumor's insidious
growth pattern and early metastatic propensity (93). This clinical reality highlights
the urgent need for novel therapeutic strategies that can overcome
the limitations of current treatments, which are often associated
with significant toxicity and suboptimal outcomes in advanced cases
(94).
The mechanism of action of WSB in NPC is reflected
mainly in two aspects: First, WSB inhibits cell proliferation by
targeting CDK4/6. It can directly bind to CDK4/6 and downregulate
the expression of CDK4/6 in NPC cells (such as HONE-1 and CNE-1
cells) and although it upregulates Cyclin D1, it inhibits the
formation of complexes between Cyclin D1 and CDK4/6, thereby
hindering Rb phosphorylation and inducing cell cycle arrest at the
G1 phase. Notably, it has no significant effect on
normal nasopharyngeal epithelial cells. Second, it enhances
radiosensitivity by promoting radiotherapy-induced DNA
double-strand breaks [at 4 h after radiotherapy, the number of
phosphorylated histone H2A variant X (γ-H2AX) foci in the
combination group was markedly greater than that in the
radiotherapy alone group: for example, 21.4 vs. 13.2 foci/nucleus
in HONE-1 cells] and delaying damage repair (at 12 h after
radiotherapy, the number of γ-H2AX foci was still greater: For
example, 7.6 vs. 3.9 foci/nucleus in HONE-1 cells) (95) (Fig. 3; Table I). In addition, WSB can induce
NPC cells to arrest at the G1 phase, which is more
sensitive to radiotherapy, and prevent them from entering the S
phase (radiation-resistant phase), thereby enhancing the killing
effect of radiotherapy on tumor cells.
Notably, this mechanism of action of WSB is highly
consistent with its performance in other malignant tumors. For
instance, in LC studies, WSB also blocks the cell cycle at the
G0/G1 phase by downregulating the expression
of CDK4/6 and Cyclin D1 (96)
(Fig. 3; Table I). Similarly, in gallbladder
cancer (GBC), a correlation between CDK4 downregulation and
G1 phase arrest has been observed, suggesting that its
conservation of cell cycle regulation may make it a potential
therapeutic agent across tumor types (97). More importantly, compared with
clinically used CDK4/6 inhibitors such as palbociclib, WSB is
safer. Although palbociclib can enhance the radiosensitivity of NPC
by inhibiting DNA damage repair, it is often accompanied by adverse
reactions such as neutropenia and peripheral neuropathy (98). By contrast, WSB at a
concentration of 40 μM exerts no significant effect on the
proliferation or cell cycle of normal nasopharyngeal epithelial
cells (NP69) and has even been confirmed to exert protective
effects on tissues such as the liver and myocardium in animal
models, which supports its low toxicity advantage in clinical
applications (65,99,100).
From the perspective of the molecular mechanisms of
radioresistance, the radioresistance of NPC cells is often
associated with efficient DNA double-strand break repair capacity
(101) (Table I). The repair-inhibiting effect
of WSB, as reflected by the delay in γ-H2AX foci, may be related to
the regulation of the ATM and ATR kinases pathway (102) (Table I). Existing studies have shown
that WSB can inhibit ATR protein kinase activity to interfere with
the DNA damage response, and this mechanism may further explain its
radiosensitizing effect in NPC. In addition, the synergistic effect
of WSB and radiotherapy in 3D organoid models (markedly reduced
activity of HONE-1 organoids) is more consistent with the in
vivo tumor microenvironment, verifying its effectiveness under
complex physiological conditions and providing key evidence for
translation from basic research to clinical practice. These
characteristics make WSB not only promising for improving the
radiotherapy effect of locally advanced NPC, but also potentially
applicable in combination with existing targeted drugs (such as
EBV-related signaling inhibitors) to construct multitarget
therapeutic regimens, thereby offering new ideas for overcoming the
therapeutic bottlenecks of NPC.
LC is the most commonly diagnosed malignancy
globally, with recent epidemiological data revealing ~2.5 million
new cases each year, 12.4% of all cancer diagnoses worldwide and
1.8 million annual fatalities, accounting for 18.7% of total cancer
mortality (1). While the advent
of molecularly targeted therapies and immunotherapies has
revolutionized treatment paradigms, the prognosis for advanced
non-small cell lung cancer (NSCLC) patients remains poor, with
5-year survival rates persistently <20% (103). This therapeutic impasse stems
primarily from two key challenges: The development of drug
resistance mechanisms and dose-limiting treatment toxicity.
At the molecular level, the WSB strongly inhibits
the ATR protein kinase activity, effectively compromising the
G2/M checkpoint integrity following DNA damage through
the suppression of critical phosphorylation events in p53 and
checkpoint kinase 1 (CHK1) (102) (Fig. 3; Table I). This distinctive mechanism of
action potentiates the efficacy of conventional DNA-damaging
anticancer therapies, presenting a novel strategic approach for
targeting ATR-dependent DNA repair mechanisms in LC treatment.
In the A549 non-small cell LC cell line, WSB
demonstrates dual cell cycle regulatory effects, inducing
G0/G1 phase arrest while simultaneously
promoting caspase-dependent apoptotic cell death. Notably, it
suppresses TGF-β1-induced EMT in A549 cells through epigenetic
silencing of ZEB1 and restoration of E-cadherin expression
(104), a key mechanism given
that EMT drives LC metastasis by disrupting epithelial adhesion via
downregulated the E-cadherin and upregulated mesenchymal markers
(Fig. 3), enabling invasive
potential, thereby equipping WSB with the capacity to inhibit
metastatic progression through suppression of the EMT pathway.
These findings collectively position WSB as a
multifaceted therapeutic candidate capable of targeting both
primary tumor growth and metastatic dissemination. The anti-cancer
mechanisms of WSB require further elucidation, particularly
regarding its dose-response relationship/optimal therapeutic
window. Systematic pharmacokinetic/pharmacodynamic studies are
needed to establish clinically effective and safe dosing
regimens.
WSB demonstrates significant antitumor activity in
PC through a multipronged mechanism that addresses both disease
progression and therapeutic resistance (15,105,106). In the context of standard
androgen deprivation therapies, which aim to block AR signaling,
which is crucial for PC cell growth (107), WSB effectively suppresses AR
signaling (108) (Fig. 3; Table I). This not only complements the
action of existing therapies but also enhances sensitivity to them,
potentially overcoming the resistance that often develops over
time. For instance, drugs such as gonadotropin-releasing hormone
agonists/antagonists and anti-androgen drugs target AR signaling,
and the modulation of this pathway by WSB could enhance the
efficacy of these drugs.
Of particular clinical relevance, WSB maintains its
efficacy against chemotherapy-resistant phenotypes. In
radiotherapy, which aims to kill cancer cells by damaging their
DNA, the ability of WSB to modulate cellular processes may enhance
the radiosensitivity of cancer cells (95) (Table I). Overall, these findings
underscore the promise of WSB as a multitarget therapeutic agent
for PC management, with potential applications in combination with
existing endocrine, chemotherapy, and radiotherapy approaches.
Gliomas, which originate from brain glial cells,
represent the most prevalent primary intracranial tumors in adults
(40-60% of central nervous system tumors) (112). WSB exerts potent antitumor
effects on glioblastoma through the induction of mitochondrial
apoptosis (via Bax/Bcl-2 modulation and caspase-3 cleavage) and
G0/G1 cell cycle arrest (through
CDK4/6-Cyclin D1 suppression) in SHG-44 and U87MG cells (113,114) (Fig. 3; Table I). RNA sequencing analyses
reveals that WSB inhibits the HOTAIR/miR-125a/mTOR pathway,
reducing glioma cell migration by 55-70% (115) (Fig. 3).
Synergy with standard therapies enhances efficacy:
Temozolomide combination therapy overcomes resistance by
suppressing O6-methylguanine-DNA methyltransferase activity and
blocking the repair of O6-methylguanine lesions. This leads to
unrepaired DNA damage, persistent double-strand breaks, and
enhanced apoptotic signaling through DNA damage response pathway
activation (116,117) (Fig. 3; Table I). Similarly, rapamycin
synergizes with WSB through dual epigenetic and mTOR-targeted
inhibition, WSB indirectly suppresses mTOR expression via
downregulation of HOTAIR expression and upregulation of miR-125a-5p
expression, whereas rapamycin directly inhibits mTOR activity.
Preclinically, WSB monotherapy achieves 68% tumor growth
inhibition, which increases to 85% when WSB is combined with
rapamycin (115,118) (Figs. 3 and 5; Table
I).
These findings position WSB as a multifaceted
therapeutic agent against glioblastoma, leveraging intrinsic
pro-apoptotic and cell cycle regulatory properties while
synergizing with conventional and targeted (rapamycin) therapies to
overcome key resistance mechanisms. Future clinical translation
should prioritize optimizing delivery strategies to penetrate the
blood-brain barrier and validating predictive biomarkers (such as
HOTAIR/MGMT expression) for patient stratification in combination
regimens.
In BC, WSB overcomes chemoresistance through
multimodal targeting: i) Chemosensitization: STAT3 is often
overactivated, which contributes to the upregulation of P-gp, a
major efflux pump responsible for pumping chemotherapeutic drugs
out of cancer cells, leading to drug resistance (119,120). WSB acts by inhibiting STAT3
signaling. As reported in studies on other cancer types, such as
neuroblastoma, the activation of STAT3 can protect cells from
apoptosis and is associated with drug resistance (121) (Fig. 3). By blocking the STAT3
phosphorylation and nuclear translocation, WSB effectively
downregulates the expression of P-gp in MCF-7/ADR cells. This
downregulation reverses the efflux of doxorubicin (DOX), thereby
increasing the intracellular concentration of DOX. As a result, the
IC50 of DOX in MCF-7/ADR cells is markedly reduced from
12.3 to 2.8 μM, enhancing the sensitivity of cancer cells to
chemotherapeutic agents (122)
(Fig. 3; Table I); ii) by blocking the
TGF-β/NOX4/ROS signaling, WSB inhibits vimentin and Snail
expression, reducing metastatic potential in 4T1-Luc models (lung
nodules ↓65%) (52,104,123) (Fig. 3); and iii) WSB polarizes
tumor-associated macrophages (TAMs) toward the antitumor M1
phenotype, increasing the expression of the M1 marker CD86 and
upregulating M1-characteristic IL-12. In triple-negative breast
cancer (TNBC) cells, WSB suppresses programmed cell death ligand 1
(PD-L1) and high levels of PD-L1 bind to T-cell PD-1, inhibiting
T-cell activation and cytotoxicity. By reducing PD-L1 expression,
WSB enhances T-cell recognition and the killing of cancer cells,
strengthening antitumor immune responses in the BC microenvironment
(23,124) (Fig. 3; Table I). Preclinical studies have
demonstrated that WSB monotherapy achieves 58% tumor growth
inhibition in estrogen receptor (ER) + BC xenografts, synergizing
with tamoxifen to achieve 82% suppression (Fig. 5).
Building on its dual anti-inflammatory and
chemosensitizing actions, WSB warrants clinical prioritization in
endometritis and TNBC, conditions with unmet therapeutic needs.
Synergistic strategies (such as PD-1 inhibition) could amplify
STAT3/PD-L1 blockade, while nanotechnology may overcome
bioavailability barriers. The mechanistic exploration of
AR-mitochondrial crosstalk in orchitis could redefine the
management of male infertility. Cross-disciplinary innovation will
catalyze WSB's transition to transformative therapies.
Osteosarcoma, the most prevalent malignant bone
tumor in adolescents, has a poor prognosis, especially in
metastatic cases (125-127) (Fig. 3). WSB inhibits osteosarcoma
progression by targeting circ_0009112/miR-708-5p and by suppressing
migration and invasion via the PI3K/AKT pathway while inducing
apoptosis (128,129) (Fig. 3; Table I). It also blocks Wnt/β-catenin
and PI3K/AKT signaling, arresting the cell cycle at the
G1 phase, inhibiting proliferation, and reducing lung
metastasis in preclinical models without significant toxicity
(63). These findings highlight
WSB's potential as a therapeutic candidate for osteosarcoma.
As a pleiotropic bioactive compound, WSB enhances
chemotherapy efficacy while mitigating adverse effects through
multitarget modulation of oxidative stress, inflammation, and cell
death pathways. Its integration with advanced drug delivery systems
further improves pharmacokinetics, offering a paradigm for
low-toxicity precision oncology (Fig. 5).
Notably, the capacity of WSB to modulate MDR,
enhance chemosensitivity, particularly well-characterized in BC,
extends to a coordinated protective role against
chemotherapy-induced organ damage, creating a synergistic
therapeutic profile. In BC, WSB reverses DOX resistance by
downregulating the P-gp via STAT3 inhibition (122) (Fig. 5; Table II), while simultaneously
counteracting DOX-induced cardiotoxicity through p38MAPK-ATM-p53
axis regulation (130,131) (Fig. 5; Table II), thus amplifying anti-tumor
efficacy while mitigating cardiac injury. This dual action aligns
with its ability to sensitize ER+ BC to tamoxifen (achieving 82%
tumor suppression in combination) (132) (Fig. 5), demonstrating that WSB's
MDR-reversing effects are paired with tissue-specific toxicity
attenuation.
Furthermore, in cisplatin-based regimens, where
drug resistance and systemic toxicity often limit efficacy, WSB not
only enhances chemosensitivity by overcoming efflux mechanisms but
also protects normal tissues: it upregulates survivin via ERK/NF-κB
to shield renal tubules and cochlear hair cells (133,134) (Table II) and inhibits the
RAGE/NF-κB/MAPK pathways to prevent neurotoxicity (135) (Fig. 5; Table II). Similarly, for thiotepa, the
pro-oxidant activity of WSB in tumor cells (driving apoptosis) is
balanced by its suppression of excessive ROS in normal tissues,
preserving hepatic and cardiac function via GPX4-mediated
ferroptosis inhibition (136-138) (Fig. 5; Table II).
Beyond specific chemotherapeutics, WSB synergizes
with supportive agents to mitigate broader complications: In
combination with glycyrrhizic acid, it suppresses TGF-β1/SMAD2
signaling and NOX4 overexpression in bleomycin-induced pulmonary
fibrosis (139) (Fig. 5), a common side effect of
alkylating agents; in cyclosporine A-induced nephrotoxicity, it
activates Nrf2 to reduce ROS, elevate glutathione, and restore
autophagy (140) (Fig. 5), thus protecting renal function
during immunosuppressive chemotherapy regimens; and in
schistosomiasis, it enhances praziquantel efficacy while
alleviating hepatosplenic injury (141,142) (Fig. 5), a model for reducing parasitic
coinfection complications during chemotherapy.
Collectively, these findings underscore the unique
therapeutic duality of WSB in cancer chemotherapy: It not only
enhances antitumor efficacy by reversing MDR and sensitizing
malignancies (as exemplified in BC) but also safeguards normal
tissues through targeted mechanisms, mitigating the systemic
toxicity that often limits treatment tolerance. This multifaceted
profile positions WSB as a promising adjuvant in chemotherapeutic
regimens, addressing the longstanding challenge of balancing
efficacy and safety across diverse cancer types and treatment
modalities.
WSB potentiates chemotherapy through synergistic
pathway inhibition: When combined with docetaxel (DTX), WSB
downregulates phosphorylated (p-)AKT/AKT and NF-κB expression,
ultimately inhibiting cervical cancer proliferation and invasion
(143) (Fig. 5; Table II). In GC, WSB and apatinib
induce G0/G1 arrest and suppress
MMP-9-mediated metastasis (144,145) (Fig. 5; Table II). With the DOX, WSB disrupts
DNA repair by abrogating G2/M checkpoints and amplifying
apoptosis (146,147) (Table II). Moreover, Additional studies
have demonstrated that WSB can also increase the sensitivity of
glioblastoma cells (GBM U87 and A172) to the antitumor drug
temozolomide by downregulating the expression of MRP1 protein or
mRNA (116,148) (Fig. 3; Table II).
However, when WSB is co-administered with P-gp
substrate chemotherapeutic agents such as paclitaxel and
doxorubicin, it promotes the drug efflux, thereby reducing
intracellular drug accumulation in tumor cells (81,149) (Figs. 3 and 5; Table
II). Additionally, WSB downregulates organic anion transporting
polypeptide 1B1 (OATP1B1) expression, which may impair the hepatic
uptake and subsequent activation metabolism of OATP-dependent drugs
such as irinotecan (150).
Furthermore, WSB exhibits complex pharmacokinetic interactions with
FK506; by competing for CYP3A-mediated metabolism, WSB accelerates
its own clearance while simultaneously inhibiting FK506 metabolism
(149) (Table II). These findings necessitate
the preclinical-to-clinical translation via the pharmacogenomic
screening: tumors with low P-gp/MRP1 and high OATP1B1 could
prioritize WSB combinations (such as DTX/WSB in cervical cancer)
while avoiding coadministration with P-gp substrates in
ABCB1-overexpressing tumors.
In summary, WSB acts as a double-edged sword in
combination chemotherapy: On one hand, it enhances the antitumor
efficacy of drugs such as docetaxel and apatinib by inhibiting key
signaling pathways (p-AKT/NF-κB) and disrupting DNA repair
mechanisms. On the other hand, the WSB-induced upregulation of
P-gp/MRP efflux pumps and suppression of OATP1B1 may antagonize the
therapeutic effects of paclitaxel, doxorubicin, and irinotecan.
Additionally, it engages in complex pharmacokinetic competition
with CYP3A substrate drugs (such as tacrolimus). Therefore,
clinical combination strategies must be precisely designed on the
basis of drug transport and metabolic profiles to mitigate
interaction risks and maximize synergistic benefits.
MDR, driven by drug efflux, cancer stem cells and
the tumor microenvironment (TME), remains a critical clinical
hurdle (151).
Preclinical studies have demonstrated that WSB
effectively overcomes RAS-mediated resistance to EGFR inhibitors in
colorectal cancer (152)
(Fig. 6; Tables I and II). Resistance to EGFR-targeted
therapy in colorectal cancer primarily arises from tumor-intrinsic
and microenvironment-driven adaptive mechanisms: RAS/RAF mutations
(such as KRAS in 40% and BRAF V600E in 8-10% of cases) lead to
constitutive activation of downstream signaling, while bypass
pathways such as the ERBB2/MET/IGF-1R amplification or
overexpression maintain survival signals through feedback loops
(153-156). Additionally, metabolic
reprogramming (enhanced glycolysis and dysregulated lipid
synthesis) and tumor microenvironment factors (such as HGF/TGF-β
secretion by cancer-associated fibroblasts) further contribute to
drug resistance (157-159). To counteract these resistance
mechanisms, WSB synergizes with panitumumab by activating
caspase-3-dependent apoptosis and suppressing Bcl-2 expression,
thereby reversing drug resistance. This mechanism could translate
to clinical trials testing WSB + panitumumab in RAS-mutant CRC,
with Bcl-2 as a predictive biomarker (Fig. 6).
In combination with 5-FU, WSB downregulates P-gp
and MRP1, reverses MDR, and triggers autophagic death via STAT3
inhibition (33,160) (Figs. 3 and 5; Table
II). This mechanism is supported by extensive evidence that ABC
transporters (such as P-gp/ABCB1 and MRP1/ABCC1) mediate drug
efflux in CRC (161-164), and TCM compounds (such as
evodiamine and neferine) restore chemosensitivity by suppressing
these transporters (165,166). Such data support the potential
of WSB as a chemosensitizer in neoadjuvant settings, where reducing
the ABC transporter activity could increase 5-FU response
rates.
These findings confirm the potential of WSB as an
ideal chemosensitizer and provide a new strategy for the
comprehensive treatment of colorectal cancer.
WSB has been established as a promising and
clinically feasible anticancer agent (167). The core advantages of these
systems include the following: i) Passive tumor targeting
leveraging the enhanced permeability and retention effect (168); ii) enhanced active targeting
via ligand modification (169);
and iii) precise drug release enabled by the design of
pH/enzyme-sensitive carriers (170). Clinically, this is evidenced by
successful nanoscale antitumor formulations, such as the polymeric
micelle Genexol®-PM (loaded with paclitaxel), approved
in South Korea for the treatment of metastatic BC and NSCLC.
Compared with conventional paclitaxel, Genexol®-PM
markedly improved the objective response rate (ORR: 56 vs. 27%) and
reduced the incidence of neutropenia (171) (Fig. 6). Similarly, the liposomal
formulation Lipusu® (paclitaxel for injection) is
approved in China for the treatment of ovarian cancer and BC. Its
combination regimen with cisplatin effectively treats inoperable
NSCLC patients (172) (Fig. 6).
Stimulus-responsive nanotechnology have yielded the
pH-sensitive formulations in which methotrexate-modified
sorafenib/WSB micelles (methotrexate-SOR/WSB) demonstrate
remarkable tumor specificity, dissociating in the acidic tumor
microenvironment to simultaneously inhibit HCC progression and
reduce systemic toxicity (173)
(Fig. 6; Table II). With the respect to
inflammatory modulation, albumin-based nanocarriers engineered with
palmitic acid modifications (PSA systems) achieve targeted WSB
delivery to M1 macrophages, effectively suppressing NF-κB-mediated
inflammation in liver injury models while improving survival by 50%
(75 vs. 25% in controls) (174)
(Fig. 6; Table II).
Combinatorial approaches use polymeric nanosystems
that coencapsulate the WSB with doxorubicin. These factors leverage
the pH-dependent release kinetics to enhance mitochondrial
targeting in BC stem cells, demonstrating the dual benefits of
overcoming chemoresistance while preserving cardiac function
(175,176) (Fig. 6; Table II). The field has further
advanced through peptide-directed delivery platforms, including the
PFV-modified liposomes that exploit tumor-specific integrin αvβ3
overexpression to disrupt metastatic vasculogenic mimicry networks
(177) (Fig. 6; Table II), and RPV-conjugated systems
that the achieve tumor penetration while suppressing the
angiogenesis through VE-cadherin/MMP-9 regulation (178,179) (Fig. 6). Particularly innovative are
charge-mediated R8-modified vinorelbine/WSB liposomes that
concurrently inhibit EMT and prevent the treatment-limiting
myelosuppression (180,181) (Fig. 6; Table II).
Despite these compelling preclinical results,
clinical translation faces the significant hurdles associated with
Good Manufacturing Practice manufacturing. For PFV-liposomes,
extrusion-based preparation results in shear sensitivity during
scale-up, risking lipid bilayer destabilization and drug leakage
(177). The PSA platform
requires strict control of palmitic acid conjugation stoichiometry
to maintain targeting efficacy, a critical quality attribute that
is challenging to standardize in large batches (182,183). Organic solvent residues
necessitate complex purification (174), increasing production costs.
Analytical complexity is heightened in codelivery systems, where
simultaneous quantification of hydrophilic/hydrophobic drugs
requires specialized methods (177).
To bridge this translational gap, integrated
solutions are essential. These include the adoption of continuous
manufacturing approaches such as microfluidic mixing to replace
batchwise liposome extrusion (184,185), coupled with the greener
synthesis methods such as supercritical CO2-based
nanoparticle production to eliminate toxic chlorinated solvents
(186,187). The implementation of QbD
principles is essential for optimizing critical conjugation
parameters (such as reaction time and pH control) in PSA
nanoparticle fabrication, whereas advanced process analytical
technology (PAT) systems should be employed for real-time
monitoring of critical quality attributes throughout production
(188). These synergistic
advancements, spanning manufacturing innovation, sustainable
chemistry, systematic process optimization and enhanced quality
control, collectively address the key technical and regulatory
hurdles impeding clinical translation (Fig. 7).
While WSB nanocarriers exemplify the TCM-modern
oncology integration, industrial viability hinges on resolving the
material, process, and regulatory gaps, a challenge demanding
cross-disciplinary collaboration.
Further studies have demonstrated the efficacy of
Sch A in bladder cancer through inhibition of the ALOX5-mediated
activity of the PI3K/AKT signaling pathway (206) (Fig. 8; Table III). In HCC, Sch A acts via
AMPK/mTOR-dependent mitochondrial ferroptosis (207) (Fig. 8; Table III) and in PC, it activates
ROS-mediated ER stress and the JNK/MAPK signaling pathway (208) (Fig. 8; Table III). Emerging evidence also
suggests its activity against non-Hodgkin lymphoma through CD20
inhibition (209) (Fig. 8; Table III).
In addition, Sch A reverses P-gp-mediated
doxorubicin resistance via the P-gp/NF-κB/STAT3 inhibition
(210) (Fig. 8), complementing the WSB's
STAT3-dependent P-gp downregulation by disrupting
transporter-substrate interactions. It restores gefitinib
sensitivity in EGFR-resistant NSCLC (211) (Fig. 8), synergizing with Lenvatinib
(LEN) (212) (Fig. 8), expanding WSB's
chemosensitization scope to the EGFR-TKI resistance.
Innovative drug delivery platforms have augmented
the therapeutic potential of Sch A. Ultrasound-targeted microbubble
destruction with Span-PEG carriers enhances Sch A uptake in
Walker-256 hepatoma cells, inhibiting the PI3K/AKT/mTOR pathway
(213) (Fig. 8). A microemulsion system loaded
with docetaxel and Sch A overcomes esophageal cancer MDR (211) (Fig. 8), whereas long-circulating
liposomes loaded with Sch A/doxorubicin (SchA-DOX-Lip) enhance
apoptosis induction and tumor targeting in HCC (214) (Fig. 8). These advancement strategies
are directly applicable to WSB, leveraging structural similarity
for formulation optimization. Together, their complementary
mechanisms and shared delivery solutions support lignan-based
combination therapies, maximizing clinical utility.
In toxicity mitigation, SC counteracts
regorafenib-induced hepatotoxicity and cardiotoxicity via EphA2
Ser897 phosphorylation and EPHA2 restoration (217,218), complementing WSB's DOX
cardioprotection (p38MAPK-ATM-p53 axis) (130,131) (Fig. 8), with structural similarity
enabling tissue-specific cytoprotection (liver/heart vs. WSB's
cardiac focus).
SC's dual capacity supports combination strategies:
Coadministration with regorafenib to reduce toxicity while
enhancing efficacy. Formulation advances (such as targeted
delivery), adaptable from WSB's nanotechnology research, could
optimize tissue-specific distribution, maximizing its integrative
potential.
Pharmacokinetically, the STA modulates drug
metabolism to enhance efficacy: it increases the cyclophosphamide
exposure (227), selectively
inhibits CYP3A4/CYP2C8 (altering bosutinib but not imatinib
metabolism) (228) (Fig. 8) and, most notably, increases LEN
bioavailability in patients with HCC via intestinal P-gp
suppression (229,230) (Fig. 8).
SAL, a dibenzocyclooctadiene lignan that shares
structural homology with WSB, exhibits multitargeted activity
across liver diseases, from NAFLD to HCC, complementing the hepatic
effects of WSB through overlapping yet distinct mechanisms
(231,232).
In HCC, SAL targets STAT3 to inhibit proliferation
and downregulate PD-L1, enhancing CTL activity (235) (Fig. 9) and complementing anti-HCC
mechanisms of WSB [such as RhoA/ROCK1 inhibition (78-80) (Fig. 9)] by increasing the degree of
immunomodulation and WSB minimally affects liver cancer. This
convergence of metabolic, fibrotic, and immunologic regulation
positions SAL as a bridge between WSB's hepatic protection and
novel immunotherapeutic strategies in HCC.
Clinically, the ability of SAL to span
NAFLD-fibrosis-HCC progression, paired with the broader anticancer
spectrum of WSB, supports the use of combination strategies.
Formulation advances, which are adaptable to WSB research, could
optimize the pharmacokinetics of both compounds, maximizing their
synergistic potential in liver disease management.
Translational efforts should focus on optimizing
bioavailability (exploiting WSB's formulation advances),
identifying biomarkers and developing combinations, capitalizing on
the structural overlap of GA with WSB to design coordinated
regimens that maximize pathway coverage across NSCLC, osteosarcoma,
CRC and melanoma.
In hepatic fibrosis, GD selectively disrupts the
PDGF-BB/PDGFRβ cascade to suppress HSC activation and induce
apoptosis in activated HSCs (241) (Fig. 9), complementing the anti-fibrotic
effects of WSB (such as TGF-β/SMAD inhibition) by targeting PDGFRβ,
a pathway that WSB does not directly engage in, thereby broadening
lignan-mediated control of fibrosis in CCl4-induced
models. Beyond the liver, GD protects against UV-induced
keratinocyte damage via the ROS scavenging and the apoptotic
pathway inhibition while suppressing melanogenesis through the
PKA/CREB/MITF axis inhibition (242) (Fig. 9), extending the ROS-modulating
properties (shared with WSB) of the lignan class to dermatological
contexts, with structural similarity enabling both to regulate
oxidative stress, but in tissue-specific ways (hepatic vs.
cutaneous).
Translational efforts should focus on optimizing
targeted delivery systems (adaptable from formulation research on
WSB), exploring synergies with existing
antifibrotics/dermatological agents and investigating preventive
potential in high-risk populations, leveraging the structural
overlap of GD with WSB to design combination strategies that
maximize dual efficacy in hepatic and dermatological
pathologies.
In oncology, GG inhibits PI3K-AKT signaling to
induce apoptosis (via PARP/caspase-3 cleavage) and suppresses the
cell cycle (Cyclin D1/phospho-Rb downregulation) in colorectal
cancer and triggers G1 arrest in TNBC through inhibition
of the AKT activity (243,244) (Fig. 9; Table III), mirroring the ability of
WSB to target PI3K/AKT in various types of cancer but with enhanced
specificity for inhibition of the activity of PI3K, creating a
complementary strategy with respect to the broader inhibition of
WSB. As well as tumors, GG counteracts muscle wasting via myostatin
modulation and the SIRT1/PGC-1α-mediated mitochondrial
biogenesis (245) (Fig. 9) and alleviates neuropathic
pain-depression comorbidity through TNF/VEGF/GH regulation
(246) (Fig. 9), extending the multitarget
potential (shared with WSB) of the lignan class to nononcologic
contexts, leveraging structural similarity to drive pleiotropic
effects.
Translational efforts should focus on WSB progress:
Optimizing structure-activity relationships (to increase target
specificity), improving pharmacokinetics via advances in
formulation (adaptable from WSB delivery research) and identifying
biomarkers for stratification. The ability of GG to complement WSB
in oncology while expanding into other therapeutic areas
underscores the versatility of the lignan class, rooted in their
conserved dibenzocyclooctadiene scaffold.
GJ demonstrates significant potential as an
anticancer agent, exhibiting efficacy across multiple cancer types
through simultaneous targeting of diverse oncogenic pathways. In BC
models, GJ uniquely induces both classical apoptosis and
necroptosis, showing particular efficacy against
apoptosis-resistant populations that drive treatment failure and
recurrence (247). This dual
cell death mechanism addresses a critical clinical challenge in
managing aggressive BC subtypes.
The anticancer activity of GJ extends to CRC, where
it suppresses the Wnt/β-catenin pathway (a key driver of colorectal
carcinogenesis) and induces G0/G1 cell cycle
arrest (248) (Fig. 9; Table III). These coordinated actions
on oncogenic signaling and cell cycle regulation underlie its
potent antitumor effects in CRC. In glioma models, GJ adopts a
multifaceted approach: triggering mitochondrial apoptosis while
disrupting tumor metabolism via the HKII-mediated glycolysis
inhibition (249) (Fig. 9; Table III), simultaneously targeting
cell survival and energy production pathways essential for tumor
growth.
The multi-target activity of GJ its and capacity to
overcome treatment resistance position it as a promising
therapeutic candidate, necessitating further development of
optimized formulations, predictive biomarkers, and rational
combination strategies for clinical translation.
Not applicable.
LZ, YL, CL, and YT conceived and supervised this
work. LZ, YL, ZC, JM, ZH, and XS organized the literature, wrote
the manuscript and created charts. LZ and YL provided funding. Data
authentication is not applicable. All authors read and approved the
final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
The present study was financially supported by the Social
Science and Technology Research Major Project of Zhongshan (grant
no. 2021B3011) and the Guangdong Medical University Undergraduate
Innovation and Entrepreneurship Training Program (grant nos.
GDMUCX2024017, GDMU2023355 and 202510571017).
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