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Xihuang pill, an approved Chinese medicine formula (state medical permit number. Z11020073), is a commonly used adjuvant drug for cancer patients in China. Xihuang pill has a satisfactory effect in treating breast cancer in clinics, especially triple-negative breast cancer (TNBC), which is the most aggressive type of breast cancer, and finite effective therapies. However, the mechanism of Xihuang pill in treating TNBC remains unclear. The present study aims to explore the pharmacological mechanism of Xihuang pill in treating advanced TNBC. We identified the main chemical components of Xihuang pill by using HPLC-Q-TOF-MS/MS. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis shows that serum containing Xihuang pill (XS) had no obvious killing effect on any subtype of breast cancer cells, but it inhibited mammosphere colony formation of two TNBC cell lines (4T1 and HCC1806 cells) and could enhance the inhibitory effect of paclitaxel (PTX) on the proliferation of 4T1 and HCC1806 cells when combined with PTX. Seventy-six active compounds in Xihuang pill, their 300 protein targets, and 16667 TNBC stem cell–related genes were identified. The drug–herb–active compound–target gene–disease network and enrichment analyses were constructed with 190 overlapping candidate targets. Through text mining and molecular docking, the target gene NR3C2 and its active compound naringenin were selected for further validation. According to the TCGA database, we observed that a high expression of NR3C2 promoted a higher survival probability regarding overall survival (OS). In vitro experiments indicated that naringenin presented an identical effect to XS, possibly by regulating the NR3C2 expression. Overall, this study explored the effect of Xihuang pill in treating advanced TNBC cells and showed that naringenin, which is the key active compound of Xihuang pill, could lessen the stemness of TNBC cells to produce a synergistic effect on PTX by regulating the NR3C2 gene.

Glioma is the most common malignancy in the central nervous system. This study aims to disclose the impacts of Xihuang pill (XHP), a traditional Chinese formula, on glioma cell pyroptosis and relevant molecular mechanism. U251 and SHG-44 cells were treated with XHP alone or together with oe-POU4F1 and sh-STAT3. CCK8 assay detected the viability, flow cytometry evaluated pyroptosis, and microscopy observed cell morphology. LDH release was determined by the LDH kit and the levels of IL-1β and IL-18 were detected by ELISA. Immunofluorescence showed NLRP3 expression in glioma cells and western blotting measured the levels of POU4F1, STAT3, NLRP3, ASC, cleaved caspase-1, and IL-1β. The binding of POU4F1 to STAT3 was verified. Primary glioma model was established to observe tumor change by in vivo imaging, determine the levels of Ki67 and NLRP3 by immunochemistry, and detect relevant protein levels by western blotting. XHP treatment alone downregulated POU4F1 and STAT3 levels, aroused pyroptotic appearance in glioma cells such as ballooning swelling, reduced cell viability and number of pyroptotic cells, increased LDH release and IL-1β and IL-18 levels, formed NLRP3 sports in cells, and elevated the levels of pyroptosis-related proteins. However, POU4F1 overexpression or STAT3 silencing suppressed XHP-promoted pyroptosis. Mechanistically, POU4F1 acted as a transcription factor of STAT3 and regulated its transcription. In primary glioma models, XHP enhanced glioma cell pyroptosis and blocked glioma growth. XHP facilitates glioma cell pyroptosis via the POU4F1/STAT3 axis.

Breast cancer remains a major threat to women's health worldwide, with drug resistance posing a significant challenge to treatment efficacy. Xihuang Pill (XHP), a traditional Chinese medicine formula, has demonstrated anti-tumor potential in breast cancer. However, its complex composition makes elucidating its precise molecular mechanisms difficult. This study aimed to identify key targets and mechanisms of XHP against breast cancer by integrating network pharmacology with Mendelian randomization analyses based on large-scale genome-wide association study (GWAS) and expression quantitative trait loci (eQTL) datasets, and thereby overcoming the subjectivity and uncertainty inherent in traditional target prediction. Active ingredients and targets of XHP were retrieved from TCMSP and SymMap databases. Breast cancer risk-related genes were identified using summary-data-based MR (SMR) analysis integrating blood eQTL data from eQTLGen and GWAS data from FinnGen. Overlapping targets between XHP and breast cancer were analyzed. In vitro experiments, including siRNA knockdown and treatment with XHP-containing serum, were conducted on MCF-7 and MDA-MB-231 breast cancer cells to assess the roles of identified targets on cell proliferation (CCK-8 assay) and migration (wound healing assay), and to verify XHP's effects on target expression (Western blot, qRT-PCR). Network pharmacology identified 383 potential XHP targets. SMR analysis revealed 33 genes significantly associated with breast cancer risk. Intersection analysis pinpointed GSTM1 and SLC22A5 as overlapping targets. Notably, GSTM1 is a key enzyme involved in glutathione metabolism and cellular detoxification, whereas SLC22A5 (OCTN2) is a crucial transporter responsible for carnitine uptake and cellular energy metabolism. MR analysis indicated that higher expression of both genes was associated with reduced breast cancer risk. In vitro, silencing GSTM1 or SLC22A5 promoted proliferation and migration of breast cancer cells. Conversely, XHP-containing serum upregulated GSTM1 and SLC22A5 expression and significantly inhibited cancer cell proliferation and migration. XHP may inhibit breast cancer cell proliferation and migration by upregulating GSTM1 and SLC22A5, offering new insights for precision TCM therapy.

The Xihuang Pill (XHP), a venerated traditional Chinese medicine, has demonstrated significant anti-cancer capabilities. Despite its proven efficacy, the scarcity of comprehensive pharmacological studies limits the widespread application of XHP. This research endeavor seeks to demystify the therapeutic underpinnings of XHP, particularly in the realm of colorectal cancer (CRC) therapy. In this study, mice harboring CT26 tumors were divided into four groups, each administered with either XHP monotherapy, 5-fluorouracil (5-FU), or a combination of both. The tumor growth trajectory was closely monitored to evaluate the effectiveness of these anti-neoplastic interventions. Advanced techniques, including 16S-rDNA gene sequencing and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), were harnessed to scrutinize the gut microbiota and serum metabolite profiles. Immunohistochemical assays were employed to gauge the expression levels of CD4, CD8, and Foxp3, thereby providing insights into the dynamics of tumor-infiltrating lymphocytes within the tumor microenvironment. Our findings indicate that XHP effectively suppresses the initiation and progression of colorectal tumors. The combinatorial therapy of XHP with 5-FU exhibited an enhanced inhibitory effect on tumor growth. Metabolic profiling revealed that XHP induced notable metabolic shifts, particularly impacting pathways such as steroid hormone synthesis, arachidonic acid metabolism, purine biosynthesis, and renin secretion. Notably, 17α-ethinyl estradiol and α-ergocryptine were identified as serum metabolites with the most substantial increase following XHP administration. Analysis of the gut microbiome suggested that XHP promoted the expansion of specific bacterial taxa, including , , , and ., while suppressing the proliferation of others such as , , and . Immunohistochemical staining indicated an upregulation of CD4 and CD8 post-XHP treatment. This study delineates a potential mechanism by which XHP inhibits CRC tumorigenesis through modulating the gut microbiota, serum metabolites, and reshaping the tumor immune microenvironment in a murine CRC model. These findings contribute to a more profound understanding and potentially broaden the clinical utility of XHP in oncology.

Background: Drug resistance is the major cause of increasing mortality in prostate cancer (PCa). Therefore, it an urgent to develop more effective therapeutic agents for PCa treatment. Xihuang pills (XHP) have been recorded as the efficient anti-tumor formula in ancient Chinese medical literature, which has been utilized in several types of cancers nowadays. However, the effect protective role of XHP on the PCa and its underlying mechanisms are still unclear. Methods: The active ingredients of XHP were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and BATMAN-TCM. The potential targets of PCa were acquired from the Gene Cards and OMIM databases. R language and Perl language program were utilized to clarify the interaction between the PCa-related targets and the potential targets of XHP. The potential targets of XHP for prostate cancer were gathered from the Gene ontology and KEGG pathway. Furthermore, cell proliferation assays were verified by PC3 and LNCaP cells. The efficacy and potential mechanism tests were confirmed by the PCa PC3 cells and mice subcutaneous transplantation. The effects of PI3K/Akt/mTOR-related proteins on proliferation, apoptosis, and cell cycle of PCa cells were measured by the Cell Counting Kit-8(CCK8), TUNEL assay, real-time quantitative reverse transcription PCR (QRT-PCR), and Western Blotting, respectively. Results: The active components of four traditional Chinese medicines in XHP were searched on the TCMSP and Batman TCM database. The biological active components of XHP were obtained as OB ≥30% and DL ≥0.18. The analysis of gene ontology and KEGG pathway identified the PI3K/Akt/mTOR signaling pathway as the XHP-associated pathway. Collectively, the results of in vitro and in vivo experiments showed that XHP had the effect of inhibiting on the proliferation of PC3 and LNCaP cells. XHP promoted the apoptosis and restrained the cell cycle and invasion of the PC3 cells and subcutaneous transplantation. Meanwhile, the suppression of XHP on the level of expression of PI3K, Akt, and mTOR-pathway-related pathway proteins has been identified in a dose-dependent manner. Conclusion: PI3K/Akt/mTOR pathway-related pathway proteins were confirmed as the potential XHP-associated targets for PCa. XHP can suppress the proliferation of prostate cancer via inhibitions of the PI3K/Akt/mTOR pathway.

Modern Western medicine uses surgeries, chemotherapy, targeted therapy, and radiotherapy to inhibit breast cancer cells through pathways such as apoptosis, necrosis, and autophagy. However, for triple-negative breast cancer (TNBC), a highly aggressive subtype lacking targeted therapies, conventional chemotherapy often leads to severe side effects and drug resistance, thereby limiting its clinical efficacy. Immunogenic cell death (ICD) can prompt dying tumor cells to release antigens and activate anti-tumor immune responses, converting \"cold tumors\" into \"hot tumors\". This opens up a new direction for overcoming tumor drug resistance and enhancing the efficacy of traditional therapies. Additionally, Xihuang Pill (XHP) has the potential for immunomodulation and chemotherapy sensitization. Studies have found that as an ICD inducer, XHP can trigger the production of three key damage-associated molecular patterns (DAMPs): HSP membrane translocation, massive ATP release, and HMGB1 secretion. The main active components of XHP include bilirubin, volatile oil, pentacyclic triterpenoids (such as boswellic acid), and steroids (such as hyodeoxycholic acid). These components possess anti-tumor effects, as well as functions in immunomodulation, efficacy enhancement, and toxicity reduction. This article elaborates on the role and mechanism of XHP in treating TNBC from aspects such as formula analysis, the mechanism of immunogenic cell death, the anti-tumor immune effects of XHP, and its relationship with immunogenic cell death. The aim is to provide a theoretical basis for the clinical application of XHP in treating TNBC through the immunogenic cell death pathway and to promote the secondary development of this medicine.

Xihuang Pill (XHP) is mainly used to treat \"Ru Yan (breast cancer)\". Evidence-based medical evidence and showed that XHP improves the efficacy of chemotherapy and reduced chemotherapy-induced toxicity in breast cancer patients. However, the mechanism of XHP against breast cancer is not clear. The effect of XHP extract on cell half-inhibitory concentration (IC50) and cell viability of MD-MB-231 cells was detected by CCK-8 method. The cell inhibition rate of MDA-MB-453 cells were detected by MTT method. Apoptosis was detected by flow cytometry, cell transfer ability was detected by Transwell method, and cell proliferation ability was detected by colony formation assay. The expression of Notch1, β-catenin and c-myc mRNA in MDA-MB-453 cells were detected by real-time fluorescence quantitative PCR. Then, chemical informatics and transcriptomics methodology was utilized to predict the potential compounds and targets of XHP, and collect triple negative breast cancer (TNBC) genes and the data of and β-boswellic acid intervention MD-MB-231 cells (from GSE102891). The cytoscape software was utilized to undergo network construction and network analysis. Finally, the data from the network analysis was imported into the DAVID database for enrichment analysis of signaling pathways and biological processes. The IC50 was 15.08 g/L (for MD-MB-231 cells). After interfering with MD-MB-231 cells with 15.08 g/L XHP extract for 72 h, compared with the control group, the cell viability, migration and proliferation was significantly decreased, while early apoptosis and late apoptosis were significantly increased (P < 0.01). After interfering with MDA-MB-453 cells with 6 g/L XHP extract for 72 h, compared with the control group, the cell inhibition and apoptosis rate increased, while the expression of Notch1, β-catenin and c-myc mRNA decreased. (P < 0.05). The chemical informatics and transcriptomics analysis showed that four networks were constructed and analyzed: (1) potential compounds-potential targets network of XHP; (2) XHP-TNBC PPI network; (3) DEGs PPI network of -treated MD-MB 231 cells; (4) DEGs PPI network of β-boswellic acid -treated MD-MB 231 cells. Several anti-TNBC biological processes, signaling pathways, targets and so on were obtained. XHP may exert anti-TNBC effects through regulating biological processes, signaling pathways, targets found in this study.

This study aims to investigate the synergistic and attenuation mechanism of Xihuang pill in the treatment of cholangiocarcinoma (CCA), thereby providing a reliable scientific basis for the selection of postoperative treatment strategies in cholangiocarcinoma patients. In total, 120 patients with advanced CCA who underwent stent implantation were divided into control group I (n = 40), control group II (n = 40), and observation group (n = 40). The patients in control group I were only treated with a tumor immunosuppressant (tislelizumab injection), the patients in control group II were administered tumor double immunotherapy (tislelizumab injection + thymalfasin injection), and the patients in the observation group were treated with Xihuang pill combined with tumor double immunotherapy. The therapeutic effect, side effects, coagulation function, tumor markers, and immune function were compared among the three groups. Compared to the patients in control groups I and II, those in the observation group showed significantly longer activated partial thromboplastin time (APPT) and prothrombin time (PT), and lower fibrinogen (FIB) levels and platelet count (PLT) after treatment (P < 0.05). In the observation group, the levels of CD3+, CD4+, and CD4+/CD8+ increased, but the level of CD8+ decreased. The levels of CEA, CA125, CA19-9, CA242, and CA50 in serum decreased. The adverse reactions in the observation group were lower, while the objective remission rate (ORR) was significantly higher than their corresponding values in control groups I and II (42.5%vs17.5%, 27.5%) (P < 0.05). The 1-year overall survival rates of the control group I, control group II and observation group were 42.5%, 50% and 60%, and the difference was not statistically significant (P > 0.05). Xihuang Pill combined with dual immunotherapy can synergistically enhance anti-tumor efficacy and reduce treatment-related toxicity in patients with advanced CCA by regulating coagulation function and immune mechanisms.

Immune checkpoint inhibitor (ICIs)-associated cardiotoxicity is a significant cause of immune-related adverse events and mortality in cancer immunotherapy, lacking effective preventative or therapeutic strategies. Xihuang Pill (XHW), a traditional Chinese medicine with established anti-inflammatory properties and clinical use in cancer treatment and adverse event mitigation, merits investigation for its efficacy against ICIs-induced cardiac toxicity. To investigate XHW's therapeutic effects on Immune checkpoint inhibitors (ICIs)-associated cardiotoxicity and its underlying mechanisms. This study utilized mass spectrometry technology to identify the chemical components in XHW. The experimental model for ICIs-associated myocarditis was generated in BALB/c mice by immunizing them with murine cardiac troponin I (cTnI) peptide and administering anti-programmed death 1 (PD-1) antibodies to mice. Mice received varying XHW dosages (0.39, 0.78, and 1.56 mg/kg). Myocardial contractility and plasma cardiac injury markers (CK, CK-MB) were assessed. Metabolomics and transcriptomics identified key signaling pathways modulated by XHW, validated via real-time quantitative PCR (QT-PCR). In addition, a correlation analysis was conducted between key genes and differential metabolites. Mass spectrometry identified 171 components in XHW. Pharmacological studies demonstrated that XHW improved cardiac contractility, reduced plasma cardiac injury biomarkers, and attenuated myocardial injury in the myocarditis model. Integrated metabolomic and transcriptomic analyses revealed that XHW primarily modulates the HIF-1 signaling pathway, significantly upregulating mRNA expression and downregulating the mRNA expression of , and . Correlation analysis identified significant associations between 16 metabolites, including 13-tetradecynoic acid, 1-pentadecanoylglycerol, and arginyl-glycyl-aspartic acid, and these genes. These findings suggest that XHW may alleviate ICIs-associated myocarditis via HIF-1 signaling pathway, offering a promising therapeutic approach for ICIs-related cardiotoxicity.

Background: Xihuang Wan (XHW), a purgative and detoxifying agent, is commonly utilized in modern medicine as a treatment and adjuvant therapy for various malignancies, including breast cancer, liver cancer, and lung cancer. A clinical study demonstrated the potential usefulness of the combination of XHW and gemcitabine as a therapy for pancreatic cancer (PC), indicating that XHW’s broad-spectrum antitumor herbal combination could be beneficial in the treatment of PC. However, the precise therapeutic efficacy of XHW in treating pancreatic cancer remains uncertain. Aim: This study assessed the biological activity of XHW by optimizing the therapeutic concentration of XHW (Xihuang pills, XHP). We performed cell culture and developed an animal test model to determine whether XHP can inhibit pancreatic cancer (PC). We also applied the well-known widely targeted metabolomics analysis and conducted specific experiments to assess the feasibility of our method in PC therapy. Materials and Methods: We used UPLC/Q-TOF-MS to test XHP values to set up therapeutic concentrations for the in vivo test model. SW1990 pancreatic cancer cells were cultured to check the effect the anti-cancer effects of XHP by general in vitro cell analyses including CCK-8, Hoechst 33258, and flow cytometry. To develop the animal model, a solid tumor was subcutaneously formed on a mouse model of PC and assessed by immunohistochemistry and TUNEL apoptosis assay. We also applied the widely targeted metabolomics method following Western blot and RT-PCR to evaluate multiple metabolites to check the therapeutic effect of XHP in our cancer test model. Results: Quantified analysis from UPLC/Q-TOF-MS showed the presence of the following components of XHP: 11-carbonyl-β-acetyl-boswellic acid (AKBA), 11-carbonyl-β-boswellic acid (KBA), 4-methylene-2,8,8-trimethyl-2-vinyl-bicyclo [5.2.0]nonane, and (1S-endo)-2-methyl-3-methylene-2-(4-methyl-3-3-pentenyl)-bicyclo [2.2.1heptane]. The results of the cell culture experiments demonstrated that XHP suppressed the growth of SW1990 PC cells by enhancing apoptosis. The results of the animal model tests also indicated the suppression effect of XHP on tumor growth. Furthermore, the result of the widely targeted metabolomics analysis showed that the steroid hormone biosynthesis metabolic pathway was a critical factor in the anti-PC effect of XHP in the animal model. Moreover, Western blot and RT-PCR analyses revealed XHP downregulated CYP3A4 expression as an applicable targeted therapeutic approach. Conclusion: The results of this study demonstrated the potential of XHP in therapeutic applications in PC. Moreover, the widely targeted metabolomics method revealed CYP3A4 is a potential therapeutic target of XHP in PC control. These findings provide a high level of confidence that XHP significantly acts as a CYP3A4 inhibitor in anti-cancer therapeutic applications.