In recent years, the incidence and mortality of malignant tumors on a global scale continue to ascend without interruption. In 2022, there were approximately 20 million newly diagnosed cancer cases worldwide. According to demographic projections, by 2050, the number of new cancer cases will attain 35 million (Bray et al., 2024). Consequently, it is of utmost importance to identify effective treatment plans and discover new therapeutic targets for malignant tumors. Natural drugs boast abundant sources, diverse structures, and extensive activities. On this basis, the development of new antitumor drugs and prodrugs with superior efficacy has become a hot field for numerous tumor scholars at present (Ma L. et al., 2021). Among them, small molecule drugs originating from the active ingredients of natural drugs, which are diverse in variety and possess the characteristics of multiple targets, multiple signaling pathways, and extensive pharmacological activities, have obtained remarkable achievements in both antitumor drug screening and mechanism research, thereby providing new thoughts for discovering new tumor treatment strategies (Basmadjian et al., 2014; Chopra and Dhingra, 2021).

Schisandra chinensis (called bei-wuweizi in Chinese, S. chinensis) is a plant of the Magnoliaceae family. Its dried fruits are traditional Chinese medicines (Yang K. et al., 2022). Schisandrin B (Sch B) is the most notable dibenzocyclooctene-type lignan in S. chinensis (Nasser et al., 2020). At present, most of the research on Sch B focuses on its effects in protecting the liver (Hong et al., 2017; Służały et al., 2024), treating cardiovascular and cerebrovascular diseases (Chen et al., 2013; Duan et al., 2021), anti-inflammation (Ran et al., 2018; Ma Z. et al., 2021), anti-oxidation (Kopustinskiene and Bernatoniene, 2021). In addition, certain preclinical studies have indicated that Sch B possesses antitumor potential in liver cancer (Song et al., 2023; Yang and Wu, 2023), colorectal cancer (Pu et al., 2021; Co et al., 2024), breast cancer (Fei et al., 2020; Li W. et al., 2024), gastric cancer (He et al., 2022) and other cancer types through promoting tumor cell apoptosis, inhibiting tumor cell proliferation, invasion and migration. In this review, we introduce the physicochemical properties and pharmacokinetics of Sch B, systematically summarize its antitumor effects and mechanisms in different tumors through preclinical studies, analyze and predict the main targets and signaling pathways of Sch B in antitumor through network pharmacology, with the objective of providing references for its further research, development and clinical application.

In August 2024, the author carried out an extensive search in the PubMed database for relevant literature published from January 2001 to August 2024. By using a collection of keywords such as “Schisandra chinensis”, “Schisandrin B″, “Sch B″, “antitumor”, “cancer”, “molecular mechanisms” and “network pharmacology”, 806 articles were retrieved in total. When it came to the literature screening stage, strict inclusion criteria were carefully established. The literature to be incorporated was required to meet multiple conditions. In the section of “Sch B Physicochemical and Pharmacokinetic Properties”, the literature should show a high relevance to Schisandrin B and have a high citation rate. For other literature, a strong link to the antitumor effect of Schisandrin B was necessary. Among comparable literature, those with a relatively high impact factor and a high standing in the journal ranking were preferred. Additionally, recently published works were given priority. After this rigorous selection procedure, 74 articles were finally cited in this paper.

Sch B (C₂₃H₂₈O₆) manifests as white flaky crystals. It has a molecular weight of 400.46 and its melting point ranges from 120°C to 121°C. Sch B is insoluble in water but soluble in organic solvents such as ethanol and dimethyl sulfoxide (DMSO). Studies have indicated that following oral administration in rats, Sch B may possess enterohepatic circulation, predominantly accumulate in the liver, and it is mainly excreted through the kidneys in the form of metabolites. The pharmacokinetics of Sch B is related to gender, with the absolute oral bioavailability of female mice being significantly higher than that of male mice. Sch B, which is widely distributed in the ovary and adipose tissue, shows linear pharmacokinetic characteristics within a certain concentration range (10 mg/kg, 20 mg/kg and 40 mg/kg) (Zhu et al., 2013; Wang et al., 2018). Shao et al. demonstrated in a myocardial infarction mouse model study that the utilization of matrix metalloproteinase-sensitive peptide-modified PEGylated lipid nanoparticles for carrying Sch B can enhance its solubility and bioavailability (Shao et al., 2017). A study has confirmed that Sch B exerts protective effects on various normal cells including liver parenchymal cells, cardiomyocytes, neurons, renal cells, and umbilical vein endothelial cells. Different concentrations of Sch B (1.67 μg/mL, 5 μg/mL, 15 μg/mL) show no cytotoxicity to nerve cells M146L. Moreover, Sch B can significantly increase the viability of human proximal tubular epithelial cells (HK-2) at 2.5 μM, 5 μM and 10 μM (Zhu et al., 2012). In animal experiments, low, medium and high concentrations of Sch B (20 mg/kg, 40 mg/kg, 80 mg/kg) were respectively administered intragastrically to rat models of myocardial ischemia-reperfusion injury. The apoptosis of myocardial cells was inhibited and myocardial ischemia-reperfusion injury in rats was improved (Zhang et al., 2017). These findings are sufficient to indicate that Sch B is characterized by low toxicity and high safety.

In the investigations on the antitumor efficacy of Sch B, researchers have determined that Sch B predominantly exerts its tumor-suppressing function via mechanisms including inhibiting the proliferation, invasion, and migration of tumor cell lines, promoting the apoptosis of tumor cells, and suppressing tumor angiogenesis (Table 1).

Most drugs exert their effects by means of the binding of drug molecules to biological macromolecules such as proteins in the body. At present, the action targets of many bioactive molecules are still unknown. Predicting the targets of drug molecules is of great significance for the development of new drugs and the exploration of new uses for old drugs (Gfeller et al., 2013). Researchers mainly employ two approaches, namely experimentation and computation, for target prediction. The experimental method has relatively high accuracy but is rather time-consuming and laborious. In the case of conducting a large number of screening tasks, the cost is extremely high. Conversely, computational prediction consumes relatively less time. However, the reliability of current algorithms is inferior to that of the experimental method. Generally, the results obtained through theoretical calculations need further verification by experiments (Zheng et al., 2004; Forouzesh et al., 2019). Existing research has shown that Sch B is a specific inhibitor of ataxia telangiectasia and rad3 - related (ATR) protein kinase (Nishida et al., 2009). The gomisin N (GN), which is the diastereoisomer of Sch B, inhibits DNA damage checkpoint signal transduction by interacting stereospecifically with ATR (Tatewaki et al., 2013). Pan et al. discovered that Sch B could reverse the drug resistance of multiple multidrug resistance cell lines overexpressing p-glycoprotein. Furthermore, the interaction between Sch B and p-glycoprotein could fully restore the intracellular drug accumulation, thereby proving that Sch B was a novel p-glycoprotein inhibitor (Qiangrong et al., 2005).

We employed a series of network pharmacology analysis methods to explore more potential targets of Sch B in tumor therapy. Initially, the targets of Sch B were retrieved from the SwissTargetPrediction database. We selected only those targets labeled “homo sapiens” for research (http://www.swisstargetprediction.ch/). Subsequently, on the Genecards database (https://www.genecards.org/), a search was conducted with “cancer and tumor” as the keyword and a relevance score greater than 10 was set to obtain tumor targets. By intersecting the outcomes of these two components, 51 targets of Sch B acting on tumors were ultimately obtained (Figure 1A). The 51 targets were used to establish a protein-protein interaction (PPI) network on the String database (http://string-db.org/) to observe the interactions among different targets and performing KEGG analysis. The disconnected nodes were concealed, and shared proteins with a minimum interaction score of 0.9 were selected. The results indicated that Sch B might exert its antitumor efficacy by influencing signal pathways related to cell cycle, apoptosis, cell migration and invasion, which is in accordance with the existing research findings (Nasser et al., 2020) (Figures 1B, C). To determine the core targets that play a crucial role in the entire target network, these targets were analyzed in depth on Cytoscape. According to the important parameter of degree, core targets such as heat shock protein 90 alpha family class A member 1 (HSP90AA1), phosphatidylinositol - 4,5 - bisphosphate 3 - kinase catalytic subunit alpha (PIK3CA), and proto - oncogene tyrosine - protein kinase Src (SRC) can be obtained. And ATR, which has been proven to be a target of Sch B, is also among them (Figure 1D). Although we have predicted the targets of Sch B in antitumor via network pharmacology, the limitation of this method is that the prediction results are all obtained based on the calculation of protein structural similarity. Whether it truly exerts its effect through these target remains to be confirmed by more experiments.

Currently, surgery, radiotherapy and chemotherapy remain the main approaches for cancer treatment. Drawing on the current research findings on the antitumor mechanism of Sch B, it is evident that Sch B exerts its antitumor role through various means and pathways in preclinical studies. Douglas Hanahan and Robert A. Weinberg authoritatively released the fourteen major characteristics of tumors (Hanahan, 2022). Upon comparing the antitumor mechanism of Sch B, it is apparent that Sch B inhibits the progression of different tumors through six aspects, including: sustaining proliferative signaling, evading growth suppressors, enabling replicative immortality, activating invasion and metastasis, inducing or accessing vasculature, resisting cell death (Figure 2).

However, the current research on Sch B does reveal several potential limitations. Despite the identification of multiple antitumor targets of Sch B, as of now, there is a scarcity of relevant research reports on its clinical application. This deficiency significantly hampers the translation process from basic research to clinical implementation. Traditional treatment modalities, such as surgical intervention, often enable radical resection of early-stage localized tumors. During extensive long-term clinical practice, radiotherapy and chemotherapy have accumulated substantial experience and demonstrated well-defined curative efficacy in a diverse range of tumors. In sharp contrast, the clinical evidence related to Sch B remains relatively limited. Current research results are insufficient to rule out the potential for long-term or high-dose administration of Sch B to induce toxicity in specific organs or systems. This may include adverse effects on the functions of crucial organs like the liver and kidneys, as well as potential impacts on the immune system. Additionally, the current research on the interactions between Sch B and existing clinical medications is still inadequate. This deficiency has the potential to undermine the safety and efficacy of combination therapies.

Undoubtedly, as researchers embark on a more systematic exploration of Sch B’s toxicity characteristics with the aim of ensuring its safe clinical application, delving deeper into its formulation technology and developing a more efficient, stable, and targeted drug delivery system to enhance its bioavailability and therapeutic efficacy, they will also need to assess the efficacy and safety of Sch B across diverse tumor types and stages. Simultaneously, clarifying its optimal combination regimens and the appropriate patient populations is of crucial importance. On the other hand, whether Sch B can enhance the efficacy of radiotherapy and act as a radiation sensitizer is also a research direction worthy of in-depth exploration by researchers. Through these efforts, the application of Sch B in the antitumor field is expected to expand in both scope and depth. Consequently, Sch B is anticipated to emerge as a potential component of novel antitumor medications, thus offering new hope to cancer patients.