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.

WSB exerts potent antiproliferative effects in CRC by inducing G₀/G₁ phase arrest in CRC cells through cyclin D1/cyclin-dependent kinase 4/6 (CDK4/6) suppression. Concurrently, it activates the CHOP-mediated unfolded protein response, triggering caspase-dependent apoptosis (41) (Fig. 3; Table I). WSB disrupts CRC progression by downregulating the expression of SIRT1, an NAD+-dependent deacetylase that is overexpressed in 60-70% of CRC cases (42) (Table I). This inhibition increases the level of SMAD ubiquitination regulatory factor 2 (SMURF2), which targets TGF-β receptors (TβRI/TβRII) for ubiquitin-mediated degradation, thereby suppressing TGF-β signaling at the receptor level (43,44) (Fig. 3). Consequently, WSB blocks TGF-β-induced EMT through two core mechanisms: i) inhibition of the SMAD-dependent pathway, in which SMURF2 blocks the SMAD2/3 phosphorylation and nuclear translocation, downregulates the expression of the EMT transcription factors (SNAIL, ZEB, and TWIST) and restores the expression of the epithelial marker E-cadherin (45,46) (Fig. 3); ii) blocking the non-SMAD pathway, in which it inhibits the activation of PI3K/AKT/mTOR mediated by TGF-β and hinders the phosphorylation and cytoskeleton recombination of TWIST1 (42,47) (Fig. 3).

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.

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.

SA, a bioactive lignan derived from Schisandra chinensis, shares WSB's abilities to reverse MDR and target oncogenic pathways (190-193). Like WSB, which downregulates the P-gp via STAT3 inhibition (194) (Table III), SA disrupts P-gp-substrate complex formation (a novel mechanism distinct from WSB but complementary in overcoming efflux-mediated resistance) (195) (Fig. 8). It also inhibits MRP1, mirroring WSB's suppression of ABC transporters, while modulating the PI3K/AKT and ERK pathways, similar to the WSB's targeting of these cascades in various cancers (196) (Fig. 8). The favorable safety profile of SA enhances its potential as a combination partner, addressing unmet needs in the context of resistant malignancies (197).

Sch A, a dibenzocyclooctadiene lignan from Schisandra chinensis, shares a conserved core structure with WSB, driving overlapping yet complementary anticancer mechanisms (198-203).

In TNBC, Sch A induces G₀/G₁ cell cycle arrest and promotes apoptosis by modulating Wnt/ER stress signaling pathways (204) (Fig. 8; Table III). In NSCLC, Sch A regulates p53 and p21 expression; downregulates Cyclin D1, CDK4 and CDK6 and triggers mitochondria-dependent apoptosis, leading to G₁/S and G₂/M phase arrest (205) (Fig. 8; Table III). In ovarian cancer, Sch A suppresses TAM protumor phenotypes and induces G₀/G₁ phase arrest, highlighting its immunomodulatory potential (13) (Fig. 8; Table III).

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.

SC, a dibenzocyclooctadiene lignan from Schisandra chinensis, shares structural homology with WSB, suggesting its dual role in mitigating chemical toxicity and antitumor activity (215,216).

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).

Antitumorally, SC induces G₁ arrest and caspase-3-dependent apoptosis in leukemia (219) (Table III) and suppresses A549 proliferation via inhibition of the AKT1 activity (220) (Fig. 8; Table III), which aligns with the ability of WSB to target the AKT pathway in solid tumors. Its unique activation of cGAS-STING to enhance cytotoxic T/NK cell infiltration promotes WSB's TAM polarization in BC, broadening lignan-mediated immune modulation (221-223) (Fig. 8; Table III).

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.

STA, a dibenzocyclooctadiene lignan from Schisandra chinensis sharing structural homology with WSB, exhibits dual functions, direct antitumor activity and pharmacokinetic modulation, that complement the mechanisms of WSB, expanding the therapeutic scope of the lignan class (224). In GC, STA triggers ROS/JNK-mediated apoptosis while suppressing Nrf2, creating selective oxidative stress in malignant cells (225) (Fig. 8; Table III), complementing WSB's ROS regulation in tumor cells (such as BC) but with distinct Nrf2 targeting, thus broadening redox-based anticancer strategies. In HCC, it uniquely inhibits galactose/fructose/mannose utilization to starve tumors (226) (Fig. 8; Table III), extending WSB's metabolic regulation (such as AMPK/mTOR in NAFLD (62-64)) by focusing on sugar metabolism, a pathway underutilized by WSB (Fig. 8).

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).

This isoform-specific control complements WSB's broader CYP3A interactions (149), reducing off-target risks while enhancing chemotherapeutic efficacy, a critical advantage over WSB's occasional drug-drug antagonism (such as with P-gp substrates). Clinically, the synergy of STA with LEN supports its use as a 'pharmacokinetic enhancer' in HCC, paired with WSB pathway inhibition (such as TGF-β/EMT) for combined efficacy. Formulation advances, adaptable from WSB delivery research, could optimize metabolic targeting and reduce CYP-mediated interactions, with therapeutic drug monitoring (as with WSB) critical to balance synergy and toxicity. This dual activity positions STA as a valuable complement to WSB, leveraging structural similarity for coordinated, mechanism-driven combination therapies.

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 NAFLD, SAL reprograms metabolism via the miR-802/AMPK axis (233) (Fig. 9), paralleling the AMPK/mTOR activation of WSB in hepatic steatosis, with structural similarity enabling shared regulation of energy homeostasis but via unique miRNA-mediated fine-tuning. Its antifibrotic activity, driven by dual inhibition of TGF-β/SMAD and MAPK (234) (Fig. 9), aligns with WSB's suppression of TGF-β signaling in liver fibrosis, reinforcing the ability of the lignan class to target fibrotic pathways through conserved structural features.

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.

GA, a dibenzocyclooctadiene lignan from Schisandra chinensis that shares structural homology with the WSB, exhibits the broad-spectrum anticancer activity through the multitargeted pathway modulation, complementing WSB's mechanisms across diverse malignancies (236). In NSCLC, GA targets TNF, AKT1, STAT3, IL6 and PI3K/AKT (237) (Fig. 9; Table III), paralleling WSB's inhibition of PI3K/AKT and STAT3 in LC, with structural similarity enabling overlapping pathway engagement while expanding to the TNF/IL6, which WSB minimally affects. In osteosarcoma, GA enhances paclitaxel efficacy via ROS modulation and CDK4/Cyclin B1 regulation (238) (Fig. 9), mirroring WSB's chemosensitization of taxanes but with distinct cell cycle control nodes, reinforcing the synergy of lignans with taxane-based regimens. In CRC, GA induces G₀/G₁ arrest, promotes apoptosis, and suppresses EMT via MMP-2/9 inhibition (239) (Fig. 9; Table III), aligning with WSB's EMT suppression through the blockade of TGF-β activity, with GA extending coverage to MMP-mediated metastasis, a key complementary mechanism. In melanoma, it activates AMPK, ERK, and JNK (240) (Fig. 9; Table III), pathways also targeted by WSB in other cancers, highlighting conserved lignan-mediated stress signaling.

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.

GD, a dibenzocyclooctadiene lignan from Schisandra chinensis sharing structural homology with WSB, acts as a dual-target agent, modulating hepatic fibrogenesis and dermatological pathologies through mechanisms that complement WSB activity.

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.

GG, a dibenzocyclooctadiene lignan from Schisandra chinensis sharing structural homology with WSB, exhibits multimodal activity, spanning oncology, musculoskeletal and neuropsychiatric disorders, with mechanisms that complement the profile of WSB.

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.