The natural flavonoid quercetin, which exhibits a range of biological activities, has been implicated in liver disease resistance in recent research. In vivo study attesting to quercetin's protective effect against metabolic-associated fatty liver disease (MAFLD) is inadequate, however. Here, our investigation explored the potential benefits of quercetin in preventing MAFLD in C57BL/6 mice fed a high-fat diet (HFD). The results revealed that quercetin ameliorated the aberrant enhancement of body and liver weight. The hepatic histological anomalie induced by MAFLD were also mitigated by quercetin. HFD-induced imbalance in serum LDL, HDL, AST, ALT, TG, and LDH was mitigated by quercetin. Mechanically, we found that quercetin improved lipid metabolism by reducing lipogenesis proteins including ACC, FASN, and SREBP-1c and enhancing β-oxidation proteins including PPARα and CPT1A. In vitro study demonstrated that quercetin regulated hepatic lipid metabolism by targeting SREBP-1c and PPARα. Additionally, quercetin enhanced the antioxidant capacity in HFD-treated mice by downregulating Nrf2 and HO-1 expressions and upregulating SOD and GPX1 expressions. The hyper-activation of inflammation was also restored by quercetin via eliminating the phosphorylation of IκBα and NF-κB p65. Collectively, our observations highlight that quercetin exerts hepatoprotective properties in MAFLD mice by regulating hepatic lipid metabolism, oxidative stress and inflammatory response.

Melanoma is highly aggressive, metastatic with a poor prognosis. Despite significant advances in targeted therapies and immunotherapies, their efficiency limited by drug resistance. Tanshinone IIA (Tan IIA), a bioactive compound derived from Traditional Chinese plant, exhibits significant anticancer potential, which still needs more research in its complex regulatory mechanisms.

This study aimed to elucidate the putative targets and regulatory mechanisms of Tan IIA in anti-melanoma, with a focus on its role in inducing ferroptosis.

We designed the experiment to explore the effects of Tan IIA on melanoma through both in vitro and in vivo experiments and to investigate the underlying mechanisms through transcriptomics combining network pharmacology analysis.

Ferroptosis monitored by Malondialdehyde (MDA), Fe2+, reactive oxygen species (ROS) and glutathione (GSH) in vivo and in vitro. RNA sequence was performed to explore the key regulatory pathways involved in Tan IIA-induced ferroptosis. Chromatin immunoprecipitation (ChIP) and Luciferase assays were used to validate transcription factor responsible for prostaglandin-endoperoxide synthase 2 (PTGS2) regulation. Additionally, RT-qPCR, western blot, IF, IHC were aimed to evaluate the expression of target gene.

Tan IIA markedly suppresses melanoma growth in a xenograft model. The same effect performed on inhibition melanoma cells and promotion to ferroptosis with accumulation of ROS, MDA, and Fe²⁺levels and GSH consumption. RNA sequencing and public database analysis revealed that Tan IIA regulates PTGS2, the critical marker of ferroptosis, and PTGS2-knockdown attenuates Tan IIA -induced ferroptosis in melanoma cells. Furthermore, we identified that Tan IIA stimulate signal transducer and activator of transcription 1 (STAT1), a transcription factor, promoting PTGS2 expression and localized in the cell cytoplasm. Moreover, downregulation of the transcription factor STAT1 lead to PTGS2 downregulation and also inhibit ferroptosis in melanoma.

This study, the first to link Tan IIA-induced ferroptosis to the STAT1/PTGS2 axis in melanoma, identifies STAT1 and PTGS2 as novel therapeutic targets for melanoma, which demonstrates the potential of natural compounds Tan IIA in overcoming drug resistance and integrates traditional medicine with advanced molecular techniques for mechanistic exploration.

The study aimed to investigate the effect and mechanism of monotropein on renal cell carcinoma (RCC).

After monotropein and NF-κB receptor activator (RANKL) treatment, cell proliferation, invasion, and apoptosis were evaluated using CCK-8, Transwell, and flow cytometry. Primary macrophages co-cultured with monotropein-treated RCC cells were analyzed to evaluate macrophage polarization using qRT-PCR, western blot, and ELISA assays by detecting the expression of M2 markers (CD206, CD168) and cytokines (IL-10, TGF-β). Additionally, the therapeutic efficacy of monotropein was examined using an RCC mouse xenograft model.

Monotropein could inhibit the proliferation, invasion, and M2 macrophage polarization and accelerate the apoptosis of RCC cells. Mechanistically, monotropein suppressed NF-κB pathway activation in RCC cells and reduced the expression of NF-κB downstream targets, including Bcl-2, c-Myc, and MMP9. RANKL could eliminate the effect of monotropein on RCC progression. In primary macrophages co-cultured with monotropein-treated RCC cells, monotropein downregulated M2 polarization markers and cytokines, further supporting its role in modulating the tumor microenvironment. In mouse models, monotropein reduced RCC tumor growth, induced apoptosis, and blocked NF-κB pathway.

Monotropein prevents RCC malignant progression and reduces M2 macrophage polarization by suppressing the NF-κB pathway, suggesting that monotropein may serve as a potential therapeutic agent for RCC by targeting both tumor cells and the tumor microenvironment.

Maternal iron deficiency (ID) disrupts maternal and offspring health by impairing iron status and antioxidant defenses. Rapamycin is known to promote autophagy, enhance antioxidant activity, and extend lifespan. This study investigates the intergenerational effects of post-deficiency dietary interventions using normal and rapamycin-treated diets on Drosophila melanogaster. Female flies (F0) were subjected to an iron-deficient diet for 14 days, followed by a 30-day recovery period on either a normal diet or a rapamycin-supplemented diet. Some F0 females were subsequently mated with normal males to produce F1 offspring. Physiological, biochemical, and gene expression analyses were conducted on F0 flies post-chelation and post-intervention. Post-eclosion evaluations, including a 60-day survival study, were performed on both generations. In F0 females, iron chelation significantly reduced (p < 0.0001) body weight, iron levels, and antioxidant enzyme activity, while increasing glutathione (GSH) levels. Gene expression analysis revealed significant changes (p < 0.05) in iron storage (Fer1HCH), autophagy (ATG1), and telomere-related genes (dHeT-A, dTahre, dTart). While a normal diet partially restored iron levels and survival, the rapamycin-treated diet improved antioxidant defenses but had mixed effects on survival and gene expression. In the F1 generation, male and female offspring from mothers on a normal diet exhibited reduced and increased iron levels, respectively, alongside improved median survival. Rapamycin increased body weight and iron levels in female offspring but reduced their median survival. Post-deficiency dietary interventions significantly shape antioxidant responses and survival in both iron-deficient mothers and their offspring. While normal diets support recovery of iron status, rapamycin enhances antioxidant defenses but compromises survival, particularly in female offspring.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality due to resistance, metastasis, and recurrence. Unlike conventional cytotoxic therapies, Xingxiao Pills (XXP), a classic traditional Chinese medicine formula, offers a complementary approach to treating LUAD, while its non-cytotoxic anti-cancer mechanisms remain unclear.

To investigate the effect and mechanism of XXP on LUAD progression and stemness via lipid metabolism regulation.

UHPLC-MS/MS was used to analyze the chemical constituents of XXP. The effects of XXP on LUAD cell proliferation, migration, invasion, and stemness were evaluated using CCK-8, Transwell, and tumor sphere assays. A LUAD xenograft model confirmed XXP's anti-tumor effects. Transcriptomics, metabolomics, ELISA, qRT-PCR, and Western blot were used to investigate the underlying mechanisms. Kaplan-Meier (KM) survival analysis and stemness index scores were performed for LUAD patients based on the TCGA dataset. Statistical analyses were performed using Student's t-test, ANOVA, and KM survival analysis (p< 0.05 considered significant).

XXP inhibits LUAD progression in mouse and cell models by targeting lipid metabolism reprogramming. It suppresses FA synthesis, elongation, oxidation, and glycerophospholipid (GPL) metabolism while upregulating arachidonic acid (AA) metabolism. Mechanistic studies revealed that XXP attenuates tumor stemness by inhibiting PLA2G4A (cPLA2), lowering AA release, and disrupting SMO/GLI1/SOX2 signaling, an effect also observed with the cPLA2 inhibitor AACOCF3. KM analysis showed that higher PLA2G4A expression correlated with a worse 5-year prognosis in LUAD (p = 0.0047). The low GPL/high AA group (consistent with XXP's metabolic pattern) had better survival (p = 0.0028) and a lower stemness index (p< 0.0001) than the high GPL/low AA unrelated group.

Xingxiao Pill modulates GPL and AA metabolism and downregulates the PLA2G4A (cPLA2)-AA/SMO/GLI1/SOX2 axis. Through this mechanism, XXP effectively inhibits tumor growth and stemness by targeting lipid metabolism.

Myeloma-related bone disease (MBD) is a common complication of multiple myeloma (MM) that deteriorates patients' quality of life and affects overall survival. Modulating the interaction between myeloma cells and the bone marrow microenvironment may offer therapeutic potential. While certain natural medicines may regulate bone homeostasis by directly targeting osteoclasts or osteoblasts, few studies have explored the effects of intervening in myeloma cells on osteoclasts, particularly through the role of exosomes.

To investigate the inhibitory effect of Guizhi Fuling Decoction (GZFL) on bone lesions formation induced by exosomes secreted by myeloma cells and provide evidence to support the clinical application of GZFL in treating MBD.

TRAP staining and Von Kossa staining were used to evaluate the inhibition of GZFL on RANKL-induced osteoclastogenesis in vitro. Micro-CT and bone histomorphometric analyses were performed to identify the protective effect of GZFL on bone destruction in vivo. RNA immunoprecipitation (RIP), RNA-seq, and UHPLC-MS/MS were conducted to investigate the MBD targets of GZFL. A clinical trial was carried out to evaluate the efficacy of GZFL capsules in the treatment of MBD.

The main bioactive components of GZFL, paeoniflorin, quercitrin and kaempferol, could target ERK1 and downregulate its expression in MM exosomes. In vitro, GZFL treatment inhibited the promoting effect of MM exosomes on osteoclast (OC) formation, bone resorption, and activated ERK1 expression. In vivo, GZFL prolonged survival rate, inhibited the exacerbation of bone lesions caused by MM exosomes and RANKL-induced ERK1 activation in mice model. Clinical data showed that GZFL capsule combined with bortezomib (Bortezomib) and dexamethasone (PD) significantly reduced the numeric rating scale, as well as the expression levels of ERK and RANKL in bone marrow. ERK1 levels exhibited a positive correlation with both the number of bone lesions and RANKL levels. Higher ERK1 expression indicated a worse prognosis.

GZFL inhibited MBD progression by reducing MM-derived exosomal ERK1, thereby suppressing RANKL-induced ERK1 activation and the downstream OC formation. GZFL combined with PD regimen had good clinical efficacy and safety in the treatment of MBD.

Squalene epoxidase (SQLE), a key enzyme in cholesterol metabolism, remains underexplored in nasopharyngeal carcinoma (NPC). Additionally, the therapeutic potential of Fangchinoline, an alkaloid with anticancer properties, has yet to be systematically evaluated. This research investigates Fangchinoline's efficacy in NPC treatment and SQLE-related mechanisms.

Drug screening in NPC cell lines C666-1 and 5-8F identified potential candidates. IC50 values were determined using CCK-8 assays, and apoptosis, proliferation, and invasion were assessed via Annexin V/PI staining, EdU staining, and Transwell assays. Cholesterol levels were quantified using a TG kit. RNA sequencing with GO/KEGG analyses identified key pathways. Correlation analysis was performed via cBioPortal and GEPIA2 databases, protein interaction networks via STRING and Cytoscape, and survival analysis via Kaplan-Meier curves. Gene and protein expression were validated with qPCR and Western blot, and an NPC mouse model confirmed in vivo efficacy.

Fangchinoline inhibited NPC cell proliferation, induced apoptosis, and reduced cholesterol accumulation. RNA sequencing revealed that Fangchinoline downregulated SQLE expression, suppressing the PI3K/AKT pathway. Correlation and protein interaction analyses highlighted SQLE's role in NPC progression, and survival analysis confirmed its clinical relevance. By targeting SQLE and disrupting cholesterol metabolism, Fangchinoline suppressed tumor growth both in vitro and in vivo.

Our study demonstrates that Fangchinoline inhibits NPC growth by targeting SQLE and disrupting the PI3K/AKT pathway, providing new insights into SQLE as a therapeutic target in NPC.

Hepatocellular carcinoma (HCC) has a relatively poor prognosis and a high degree of malignancy. However, the therapeutic drugs are limited. In recent years, abnormal lipid metabolism and its important role in HCC has been reported, and emerging studies found that some formulae and active components of traditional Chinese medicine (TCM) can regulate abnormal lipid metabolism in HCC, showing their good application prospects. Therefore, this article summarizes the changes and the roles of lipid metabolites in HCC progression, and discusses the role of formulae and active components of TCM for the treatment of HCC based on their regulation on abnormal lipid metabolism. A deeper understanding of their relationship may help the precise use of these formulae and active components in HCC.

Non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) accounts for an increasing proportion of HCC cases. Currently, effective pharmacological options for treating both NASH and NASH-HCC remain limited, necessitating the identification of novel therapeutic agents. Our previous studies have demonstrated that ginger can ameliorate nonalcoholic fatty liver disease (NAFLD) and prevent the occurrence of NASH. The therapeutic effects and underlying mechanisms of NASH-HCC, however, remain poorly understood.

Network pharmacology, bioinformatics, single-cell RNA sequencing analysis, and molecular docking were used to identify the main active compounds, targets, and possible mechanisms of ginger in treating NASH-HCC. The anti-tumor efficacy and underlying mechanisms of the selected compound in treating NASH-HCC were validated through in vitro experimentation.

Network pharmacology, bioinformatics, and molecular docking have revealed that 6-gingerol is the main active compound of ginger in treating NASH-HCC. SRC can be an essential target gene for ginger attenuating NASH-HCC progression, while the mitogen-activated protein kinase (MAPK) signaling pathway and reactive oxygen species (ROS) play equally important roles. Single-cell RNA sequencing of the HCC patients shows that the key targets of ginger in treating NASH-HCC are distributed in tumor-associated macrophage (TAMs). It has been reported that NOX2-derived ROS in macrophages can activate Src and then regulate downstream MAPK signaling cascades. 6-Gingerol can inhibit the proliferation, migration and reduce lipid deposition of liver cancer cells in vitro. More importantly, it induces polarization TAMs to M1 and enhances proinflammatory function, which may be achieved via the NOX2/Src/MAPK signaling pathway.

This study proves that 6-gingerol, the primary active compound in ginger, plays a role in attenuating the progression of NASH-HCC by inhibiting the proliferation and migration of tumor cells, or reprogramming TAMs to the M1 phenotype via the NOX2/Src/MAPK signaling pathway and activating the TAM-mediated immune responses.

Jiedu Sangen Decoction (JSD) is widely used in the treatment of colorectal cancer (CRC) patients in southern China due to its good clinical efficacy, but the effective active ingredients are still unknown.

This study fully explored the bioactive components of JSD based on an innovative and comprehensive research strategy. Using advanced computer technology (e.g., machine learning AHP-SOM algorithm and molecular dynamics simulation) to identify the most promising bioactive components and key targets in JSD, in order to provide new perspectives for the development of natural drugs.

UPLC-MS/MS was used to screen bioactive components in JSD and rat plasma, and network pharmacology analysis combined with machine learning yielded the most promising bioactive components. RNA-seq was used to screen therapeutic targets before and after JSD acted on SW620 cells, and bioinformatics was used to analyze the clinical significance of these key targets. Molecular docking, molecular dynamics simulation, and experiments verified the most promising bioactive components and their therapeutic targets.

JSD exhibited a strong pro-apoptotic effect on CRC in vitro. UPLC-MS/MS screened out 18 prototype components and 8 possible metabolites of JSD entering the blood. Network pharmacology combined with machine learning identified the three most promising bioactive components. RNA sequencing and bioinformatics analysis revealed six key targets of JSD against CRC. Molecular docking and molecular dynamics simulations proposed the most promising "small molecule drug-target protein" combinations, and SPR and MST demonstrated the direct binding between them: Resveratrol - CA9, Genistein - NOTUM, and Afzelin - DPEP1. Molecular biology experiments found that resveratrol may promote CRC apoptosis through the CA9/PI3K/AKT signaling pathway, and genistein targets NOTUM to downregulate β-catenin expression to inhibit CRC proliferation.

It is feasible to develop a novel and comprehensive research strategy to fully explore bioactive components of JSD and provide full support for natural drug development.

Exploring the anti-tumor molecular mechanisms of traditional Chinese medicines has become an important strategy to develop novel anti-tumor drugs in the clinic. Several pharmacological studies have reported the antioxidant, antibacterial, anti-inflammatory, and anti-tumor effects of clove. Previously, we have shown that the active fraction from clove (AFC) can inhibit the growth of tumor cells, particularly colon cancer cells, in vitro. However, the mechanism of action regarding the anti-colon cancer activity of AFC, especially in aerobic glycolysis, has not been adequately investigated. In this study, we found that AFC significantly inhibited the growth of five types of colon cancer cells, downregulated the mRNA and protein levels of M2-type pyruvate kinase (PKM2), and reduced aerobic glycolysis capacity. Transfection of PKM2-siRNA mimicked the inhibitory effects of AFC on aerobic glycolysis in colon cancer cells. Furthermore, the highly expressed, tumor-specific targets c-myc and cyclin D1 in cells were also found to be downregulated following the action of AFC. In the HCT116 cell xenograft nude mice models, the results after AFC administration were consistent with those of the cellular experiments, while AFC caused less liver injury and weight loss than the conventional chemotherapeutic agent 5- fluorouracil (5-FU). In conclusion, AFC inhibits colon cancer growth by downregulating PKM2 to inhibit aerobic glycolysis and reduce the tumor-specific high expression of c-myc and cyclin D1. Future work should explore how it downregulates pyruvate kinase (PK) in the first place, along with the intrinsic mechanism between the downregulation of PKM2 and the downregulation of c-myc.

Esophageal cancer, a malignant neoplasm originating from the epithelial cells of the esophagus, predominantly manifests as esophageal squamous cell carcinoma (ESCC) in approximately 90% of cases in China. Cisplatin-based chemotherapy regimens remain the first-line therapeutic option for ESCC, however, the five-year overall survival rate of patients is disappointingly low. Oridonin, a bioactive diterpenoid extracted from the traditional Chinese medicine herb Donglingcao, has demonstrated inhibitory effects against various malignancies. Currently, research on the combination of oridonin and cisplatin for the treatment of ESCC is limited. This study aims to elucidate the potential synergistic anti-cancer effects of oridonin in combination with cisplatin on ESCC, along with the underlying synergistic molecular mechanisms. In vitro experiments revealed that the combination of oridonin and cisplatin could synergistically inhibit ESCC cell proliferation, migration, invasion. The synergistic effect also induced cell cycle arrest and promoted apoptosis via the mitochondrial pathway by augmenting NOXA transcriptional activity and activating the NOXA-BCL2 axis. In vivo experiments corroborated these findings, showing a marked reduction in the growth of subcutaneous xenograft tumors in mice treated with the combination, without exacerbating the cisplatin-associated side effects such as weight loss or hepatic and renal toxicity. In conclusion, the combination of oridonin and cisplatin can synergistically inhibit the development of ESCC through the activation of the NOXA-BCL2 axis signaling pathway. This treatment is both safe and effective,presenting a promising prospect for combined therapeutic application in ESCC management.

Glioblastoma multiforme (GBM), classified as a grade IV astrocytoma, is the most aggressive and deadly form of glioma, characterized by rapid progression, extensive genetic heterogeneity, and resistance to conventional therapies. Despite advancements in surgical techniques, radiation therapy, and the frontline chemotherapeutic agent temozolomide, the prognosis for GBM patients remains poor, with a median survival of 15 months and a 5-year survival rate of approximately 7 %. The absence of effective long-term treatments underscores the urgent, unmet clinical need for novel therapeutic strategies to improve patient outcomes. Natural products, particularly alkaloids, have garnered attention as a rich source of bioactive compounds with diverse pharmacological properties. Alkaloids, a structurally diverse group of natural products, are renowned for their chemotherapeutic properties and ability to cross the blood-brain barrier (BBB), making them promising candidates for glioma therapy. This review systematically examines all reported heteroaromatic alkaloids with documented anti-glioma activities, highlighting their mechanisms of action where available. By providing a comprehensive resource, it aims to facilitate the identification and optimisation of alkaloid-based compounds for glioma-targeted drug discovery. Additionally, this review emphasizes the importance of incorporating natural products into the drug development pipeline to address the pressing challenges associated with glioma, particularly GBM treatment.

Alpinia officinarum Hance (A. officinarum), a perennial herb used in the treatment of digestive system cancers, holds significant value for the Li people of Hainan as a traditional Chinese medicine. (R)-5-hydroxy-1,7-diphenyl-3-heptanone (DPHC), a diarylheptanoid component is derived from A. officinarum. Diarylheptanoids have demonstrated anti-proliferative effects on breast cancer cells, neuroblastoma cells, and other tumor cells. However, the pharmacological activity of DPHC in improving hepatocellular carcinoma (HCC) remains undefined.

To elucidate the anti-HCC effects of DPHC derived from A. officinarum and explore its underlying mechanistic pathways both in vivo and in vitro.

The effects of DPHC on HCC cell lines were evaluated in vitro using cell counting kit-8, EdU cell proliferation assays, a wound healing assay, a three-dimensional tumor spheroid model, and flow cytometry. The ability of DPHC to ameliorate HCC was assessed in vivo via a nude mouse subcutaneous xenograft tumor model, serum biochemical marker detection, and hematoxylin-eosin staining. The molecular mechanism of DPHC in HCC was elucidated through a combination of transcriptome sequencing, cell transfection, immunohistochemistry assay, immunofluorescence staining, quantitative reverse transcription-PCR, and western blot analysis.

DPHC induced significant G0/G1 phase arrest and apoptosis in HepG2 and HCCLM3 cells while also markedly inhibiting tumor growth in nude mice. Mechanically, DPHC directly interacted with centromere-associated protein U (CENPU) to suppress its expression. The reduced expression of CENPU results in decreased interaction with the transcription factor E2F6, thereby affecting the transcriptional activity of the transcription factor E2F1. This subsequently inhibits the expression of downstream cell cycle factors (CCND1, CDK4, and CDK1) and increases apoptosis factors (Caspase 3 and Caspase 9).

DPHC from A. officinarum specifically modulates the function of CENPU in the cell cycle and apoptosis to ameliorate HCC. Our study revealed the anti-HCC effect and underlying mechanism of DPHC, offering new insights and potential targets for HCC treatment.

In China, sodium cantharidinate/vitamin B6 (SC/VB6) injection has been approved since 2002 for the treatment of lung cancer and primary liver cancer. In addition to these authorized indications, clinical application of SC/VB6 is also common in various other types of cancer. However, there is a lack of comprehensive understanding on this topic. Thus, this systematic review and meta-analysis aims to consolidate evidence regarding the efficacy and safety of off-label use of SC/VB6 in oncology.

International databases including PubMed, Embase, Cochrane Library, Web of Science, and CINAHL Plus, as well as Chinese databases including China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), and Wanfang, will be searched from the inception to 31 December 2024. Comparative studies that evaluated the add-on effect of SC/VB6 to conventional cancer treatments against the use of conventional treatments alone will be considered in the scope of this review. The primary outcomes are objective response rate and performance status. Secondary outcomes are disease control rate (DCR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), and adverse events (AEs). Depending on heterogeneity, data will be synthesized using either the Mantel-Haenszel fixed-effect or the DerSimonian and Laird random-effect model. Subgroup analyses will be conducted for the following variables: type of cancer, study design, SC/VB6 dosage, treatment duration, and combined therapies, provided that each subgroup contains at least two studies. Sensitivity analyses will be performed on efficacy outcomes. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) will be utilized to appraise the overall quality of evidence.

This review will encompass both randomized controlled trials (RCTs) and cohort studies, thereby enabling us to synthesize and assess evidence across experimental and real-world observational settings. Our findings will contribute to a better understanding on the benefit-risk profile regarding the off-label use of SC/VB6 in oncology, guiding the trajectory of future research, and offering a robust scientific foundation to inform clinical and regulatory decision-making process.

PROSPERO CRD42024504977.

Colorectal cancer (CRC) is one of the deadliest cancers globally, ranking as the third most prevalent and second most lethal malignancy worldwide. The standard treatment for CRC typically involves a combination of surgery, radiotherapy, and chemotherapy. Despite advancements in CRC treatment, the prognosis remains unsatisfactory, primarily due to unclear mechanisms underlying tumorigenesis and the aggression of CRC. The aberrant activation of the PI3K/AKT pathway is frequently implicated in the initiation, progression, and metastasis of CRC. Studies have demonstrated that shikonin (SK) exerts anti-cancer effects. In this study, we evaluated the anti-tumor activities of a series of semi-synthesized SK derivatives against CRC cells. Our findings revealed that the SK derivative (M12) significantly inhibited the proliferation and colony formation of CRC cells, reduced cell migration, and induced apoptosis. Mechanistically, M12 enhanced the production of reactive oxygen species and downregulated the mitochondrial membrane potential, ultimately leading to mitochondrial apoptosis. Furthermore, M12 exhibited anti-CRC effects by modulating the PI3K/AKT signaling pathway and significantly suppressed tumorigenicity without causing notable adverse effects in mice. Therefore, targeting the PI3K/AKT pathway could be a promising treatment for CRC. M12 appears to be a promising candidate for the effective and safe treatment of CRC.

Metabolic syndrome (MetS) is a cluster of interrelated metabolic abnormalities that significantly elevate the risk of cardiovascular disease, obesity, and diabetes. Flavonoids, a diverse class of bioactive polyphenolic compounds found in plant-derived foods and beverages, have garnered increasing attention as potential therapeutic agents for improving metabolic health. This review provides a comprehensive analysis of the therapeutic effects of flavonoids in the context of the MetS, with a particular focus on their modulation of the AMP-activated protein kinase (AMPK) pathway. AMPK serves as a central regulator of cellular energy balance, glucose metabolism, and lipid homeostasis, making it a critical target for metabolic intervention. Through a systematic review of the literature up to April 2024, preclinical studies across various flavonoid subclasses, including flavonols, and flavan-3-ols, were analysed to elucidate their mechanistic roles in metabolic regulation. Many studies suggests that flavonoids enhance glycolipid metabolism by facilitating glucose transporter 4 (GLUT4) translocation and activating the AMPK pathway, thereby improving glycemic control in diabetes models. In obesity-related studies, flavonoids demonstrated significant inhibitory effects on lipid synthesis, reduced adipogenesis, and attenuated proinflammatory cytokine secretion via AMPK activation. These findings show the broad therapeutic potential of flavonoids in addressing the MetS and its associated disorders. While these preclinical insights highlight flavonoids as promising natural agents for metabolic health improvement, it is important to note that their excessive concentrations may disrupt these pathways, potentially leading to metabolic imbalance and cytotoxicity. Further studies and clinical trials are essential to determine optimal dosing regimens, formulations, and the long-term safety and efficacy of flavonoids. This review highlights the importance of flavonoids for natural interventions targeting MetS and its comorbidities, offering a foundation for future translational research.

This study aimed to investigate how Tanshinone IIA (Tan IIA) affects gastric cancer cell (MGC803) proliferation under anaerobic conditions, which are linked to drug resistance and tumor growth. The proliferation of MGC803 cells under both aerobic and anaerobic conditions in response to Tan IIA was assessed using the Cell Counting Kit-8 (CCK-8) assay. To elucidate the molecular mechanisms underlying these effects, proteomics analysis was performed following treatment with 50 µmol/L Tan IIA, focusing on alterations in Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Additionally, in vitro evaluations such as glucose uptake, lactate production, and adenosine triphosphate (ATP) synthesis were employed to validate the alterations in glycolytic activity observed in anaerobic cells treated with Tan IIA. Under anaerobic conditions, Tan IIA enhanced the inhibitory effect on the proliferation of MGC803 cells. Proteomics data revealed that a total of 6629 proteins were identified and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), with 2604 proteins exhibiting significant changes (fold change > 2 or < 0.5, P < 0.05). KEGG analysis highlighted the perturbation of glycolytic pathway by Tan IIA under anaerobic conditions, accompanied by reduced glucose uptake, lactate production, and ATP synthesis. Additionally, a downregulation of glycolytic enzyme expression was observed at both the mRNA and protein levels, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase A (LDHA), phosphofructokinase 2 (PFKP), and pyruvate dehydrogenase (PDH). Tan IIA inhibits the proliferation of MGC803 cells by disrupting the glycolysis under anaerobic conditions, offering a potential treatment for anaerobiosis-resistant solid tumors.

Colorectal cancer (CRC) is the third most prevalent form of cancer worldwide. Among patients with CRC, colorectal liver metastasis (CRLM) is the foremost direct contributor to mortality. In recent years, immunotherapy has swiftly risen to prominence as a vital approach for treating a range of solid tumors, including CRC. We present a unique case of a patient suffering from CRLM, with the goal of offering an insightful example and relevant references for the treatment of CRLM.

We report a patient who experienced liver metastasis after undergoing successful surgical removal of CRC, with the postoperative pathological stage identified as pT4N2aM0. The patient has been receiving a combination treatment of Western and Traditional Chinese Medicine. Regular assessments of the patient's condition have been conducted, encompassing evaluations of serum carcinoembryonic antigen levels, carbohydrate antigen 199, and observations of the tongue complexion and its coating. The patient achieved clinical remission after anti-programmed death-1 immunotherapy when various systemic therapies failed. Since the diagnosis of CRLM, the patient has survived for more than 6 years, surpassing the expected survival time for those with advanced CRC.

This case illustrates the considerable promise of anti-programmed death-1 immunotherapy in managing CRLM, especially in scenarios of drug resistance and disease progression.

Inflammation plays a key role in the development of neurodegenerative disorders that are currently incurable. Licochalcone A (LCA) has been described as an emerging anti-inflammatory drug with multiple therapeutical properties that could potentially prevent neurodegeneration. However, its neuroprotective mechanism remains unclear. Here, we investigated if LCA prevents cognitive decline induced by Lipopolysaccharide (LPS) and elucidated its potential benefits. For that, 8-week-old C57BL6/J male mice were intraperitonially (i.p.) treated with saline solution or LCA (15 mg/kg/day, 3 times per week) for two weeks. The last day, a single i.p injection of LPS (1 mg/kg) or saline solution was administered 24 h before sacrifice. The results revealed a significant reduction in mRNA expression in genes involved in oxidative stress (Sod1, Cat, Pkm, Pdha1, Ndyfv1, Uqcrb1, Cycs and Cox4i1), metabolism (Slc2a1, Slc2a2, Prkaa1 and Gsk3b) and synapsis (Bdnf, Nrxn3 and Nlgn2) in LPS group compared to saline. These findings were linked to memory impairment and depressive-like behavior observed in this group. Interestingly, LCA protected against LPS alterations through its anti-inflammatory effect, reducing gliosis and regulating M1/M2 markers. Moreover, LCA-treated animals showed a significant improvement of antioxidant mechanisms, such as citrate synthase activity and SOD2. Additionally, LCA demonstrated protection against metabolic disturbances, downregulating GLUT4 and P-AKT, and enhanced the expression of synaptic-related proteins (P-CREB, BDNF, PSD95, DBN1 and NLG3), leading all together to dendritic spine preservation. In conclusion, our results demonstrate that LCA treatment prevents LPS-induced cognitive decline by reducing inflammation, enhancing the antioxidant response, protecting against metabolic disruptions and improving synapsis related mechanisms.

Study explored the synergistic anti-tumor effects of a combination of compounds from Traditional Chinese Medicine, including rosmarinic acid (RA), chlorogenic acid (CA), and scoparone (SCO), in the formulation of multivesicular liposomes (MVLs). Optimization of formulations and process parameters was essential to achieve effective liposomal encapsulation and optimal release profiles for these three compounds with diverse properties. Traditional trial-and-error approaches are inefficient for the optimization of complex multi-compound MVLs. We developed a new formulation optimization model, which could address this issue by predicting the optimal multi-compound MVLs formulation. Our machine learning model integrated support vector machine regression (SVR) algorithm and cuckoo search (CS) algorithm, resulting in three CS-SVR models to predict single-compound MVLs. The CS algorithm, with various weighting rules, was then applied to search the best formulation parameters across three CS-SVR models and to maximize the encapsulation efficiency for all three compounds. The multi-compound MLVs were subsequently prepared under the predicted conditions, achieving an optimized particle size of 15.12 µm, with encapsulation efficiencies of 82.93 ± 2.43% for CA, 82.22 ± 1.25% for RA, and 95.60 ± 0.18% for SCO. The predicted optimal multi-compound MVLs were further validated through in vitro characterization and in vivo anti-tumor experiments, showing a promising synergistic anti-tumor effect consistent with in vitro results. This model accurately predicted optimal encapsulation conditions, which were validated experimentally, demonstrating improved encapsulation efficiencies and reduced trial-and-error iterations. Collectively, our model provides a predictive pathway for multi-compound MVLs formulation, indicating the ability of this model to significantly reduce experimental burden and accelerate formulation development.

Uncaria rhynchophylla (Miq.) Miq. ex Havil. (UR), a traditional Chinese medicinal plant, plays an active role in neuroprotection. Clinical medication and modern pharmacological studies have proved the efficacy of UR against Parkinson's disease (PD), with alkaloids being recognized as the main bioactive components. But the therapeutic effect and mechanism of U. rhynchophylla alkaloid extract (URA) against PD need further exploration.

The study aimed to investigate the therapeutic effect and potential mechanism of URA on PD.

LC-MS methodology was used to evaluate the chemical constituents of URA. The anti-PD activity of URA in vivo was measured on the mouse and rat models of PD. Neuroprotective effect of URA on PC12 cells was measured by MTT assay. Dopamine (DA) and its metabolites were detected by LC-MS for probing the protection ability on dopaminergic neurons. The differentially expressed proteins between model group and URA administrated group were analyzed by proteomics, suggesting oxidative phosphorylation as possible pathway of URA. Considering the critical role of mitochondria in oxidative phosphorylation, JC-1 staining, MitoSOX staining, transmission electron microscopy (TEM) observation and adenosine triphosphate (ATP) levels detection were used to analyze the effects of URA on mitochondrial morphology and function. Biolayer interferometry (BLI) was used to search for the possible UCHL1-bonding compounds in URA.

URA significantly mitigated the behavioural defects by improving coordination, shortening the time to climb down the whole pole (T-LA) and increasing the forelimbs' muscle strength of MPTP-induced PD mice and 6-OHDA-induced PD rats. In addition, URA improved tyrosine hydroxylase expression in dopaminergic neurons by immunohistochemistry (IHC) staining, and thus increased the neurotransmitter levels of DA and relevant metabolites. Furthermore, URA promoted mitophagy as reflected by a significant decrease in reactive oxygen species (ROS) generation, an increase in ATP levels and clearance of damaged mitochondria. Subsequently, Ubiquitin C-terminal hydrolase 1 (UCHL1), which is associated with the mitochondrial dysfunction in PD, is suggested to be a promising target based on the proteomics result, and proved by the blocked protective effects of URA by UCHL1 inhibitor. Furthermore, hirsuteine (HTE) was identified as a potential active compound of URA binding to UCHL1 by BLI, and the binding capacity and site were verified by surface plasmon resonance (SPR) and molecular docking.

This work demonstrates that URA exerts effective neuroprotective activity against PD via activation of mitophagy with the involvement of UCHL1, and HTE may be a potential active compound of URA.

In recent years, with the deepening understanding of the biological mechanisms underlying tumorigenesis, metabolic reprogramming has emerged as a pivotal process in cancer initiation, progression, and treatment resistance, gradually paving the way for new avenues in precision oncology. Natural herbal ingredients, characterized by their multi-target engagement, low toxicity, and wide-ranging biological activities, exhibit unique advantages in anti-cancer therapy. Nonetheless, the clinical application of these components has been constrained by issues such as poor solubility, low bioavailability, and inadequate stability when administered through traditional delivery methods. The advent of multifunctional nanoformulations has offered solutions to these challenges, substantially advancing the utilization of natural herbal components in precision therapy targeting tumor metabolic reprogramming. This article provides a comprehensive review of the multidimensional features of cancer metabolic reprogramming and its intricate regulatory network, highlighting the latest advancements in metabolic regulation, targeted delivery, and precision therapy achieved through natural herbs and their multifunctional nanomedicines. It also offers insights into future directions in this field. We are justified in believing that continued breakthroughs in this area will usher in safer and more effective treatment options for cancer patients, heralding a new chapter in cancer therapy.

The annual rise in gastrointestinal cancer cases is evident, yet the occurrence of multiple primary malignancies remains comparatively uncommon. In recent years, immunotherapy has swiftly emerged as the leading treatment for several solid tumors, including gastrointestinal cancers. Single treatments might be ineffective, necessitating the need for comprehensive integrative medicine.

This study reports a case of multiple cancers, including colorectal and gastric cancers. Diverse systemic treatments, like capecitabine, the combination of capecitabine and paclitaxel liposome, as well as capecitabine with toripalimab, were unsuccessful. Nevertheless, prolonged survival was attained through anti-PD-1 immunotherapy complemented by alternative medicine approaches. The patient has exceeded a 35-month survival post-initial diagnosis and 20-month survival since the subsequent diagnosis, markedly surpassing the prognosis often associated with advanced-stage multiple cancers.

In summary, this case underscores the potential effectiveness of a holistic, integrative medical approach in managing advanced multiple malignancies amid drug resistance and disease progression.

Non-small cell lung cancer (NSCLC), although considered non-immunogenic, is often resistant to chemotherapy agents during the course of treatment in clinical patients. Melittin (C131H229N39O31, CAS: 20449-79-0), the major component of honey bee venom, is a promising anticancer drug. However, the mechanism employed by melittin to reverse chemotherapy resistance of NSCLC cells remains unknown. In this study, the Cell Counting Kit 8, ethynyl deoxyuridine assay, and other assays were utilized to elucidate the melittin effects upon cell proliferation. Proteomics, lung cancer (LC) tissue chip, and Western blot analysis were used to identify potential targets of melittin. A549/DDP cells were employed to investigate the melittin effects against cisplatin resistance. Also, an in vivo animal experiment was conducted to further clarify the regulatory function of melittin towards cisplatin resistance of A549/DDP cells. Results showed that melittin inhibited malignant progression of A549/DDP cells by down-regulation of pyruvate dehydrogenase kinase 3 (PDK3)-mediated aerobic glycolysis and inhibition of heat shock factor 1 (HSF1) expression. The therapeutic effect of melittin was increased by combination with KNK437 and impaired chemotherapy resistance regarding A549/DDP cells via reversing aerobic glycolysis. The in vivo experiments confirmed that melittin incremented A549/DDP cell cisplatin sensitivities. Collectively, the data suggested that melittin suppressed aerobic glycolysis by regulating HSF1/PDK3, which incremented cisplatin sensitivity of A549/DDP cells. It may provide a new treatment method for chemotherapy resistance in clinical NSCLC patients.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Gefitinib is a first-line treatment for NSCLC. However, its effectiveness is hindered by the development of drug resistance. At present, Shenqi Fuzheng injection (SFI) is widely accepted as an adjuvant therapy in NSCLC.

This study investigates the molecular mechanism of SFI when combined with gefitinib in regulating cell progression among EGFR-TKI-resistant NSCLC.

We established gefitinib-resistant PC9-GR cells by exposing gefitinib escalation from 10 nM with the indicated concentrations of SFI in PC9 cells (1, 4, and 8 mg/mL). Quantitative real-time polymerase chain reaction was performed to assess gene expression. PC9/GR and H1975 cells were treated with 50 ng/mL of interleukin (IL)-22 alone or in combination with 10 mg/mL of SFI. STAT3, p-STAT3, AKT, and p-AKT expression were evaluated using Western blot. The effects on cell proliferation, clonogenicity, and apoptosis in NSCLC cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation and flow cytometry assays.

SFI treatment alleviated the development of gefitinib resistance in NSCLC. PC9/GR and H1975 cells treated with SFI significantly exhibited a reduction in IL-22 protein and mRNA overexpression levels. SFI effectively counteracted the activation of the STAT3/AKT signaling pathway induced by adding exogenous IL-22 to PC9/GR and H1975 cells. Moreover, IL-22 combined with gefitinib markedly increased cell viability while reducing apoptosis. In contrast, combining SFI with gefitinib and the concurrent treatment of SFI with gefitinib and IL-22 demonstrated the opposite effect.

SFI can be a valuable therapeutic option to address gefitinib resistance in NSCLC by suppressing the IL-22/STAT3/AKT pathway.

This study was to investigate the mechanism of Changma Xifeng tablet, a traditional Chinese medicine in the treatment of Tourette syndrome. Network pharmacology was utilized to pinpoint blood-entering constituents of Changma Xifeng and explore their potential targets. Additionally, differential microRNA expression analysis was conducted to predict Tourette syndrome-associated targets, complemented by molecular docking and dynamics simulations to support the interactions of the active compounds with these targets. The study identified 98 common targets between Changma Xifeng and Tourette syndrome, which may be involved in the treatment process. A protein-protein interaction network and a drug-active ingredient-disease target network highlighted the formulation's multi-component, multi-target therapeutic approach. Eight pivotal targets-AR, GRM5, MET, RORA, HTR2A, CNR1, PDE4B, and TOP1-were identified at the intersection of microRNA and drug targets. Molecular docking revealed 12 complexes with favorable binding energies below - 7 kcal/mol, specifically: AR with Alfacalcidol, TOP1 with Albiflorin, GRM5 with Arachidic Acid, GRM5 with Palmitic Acid, AR with Arachidic Acid, AR with 2-Hydroxyoctadecanoic Acid, RORA with Pinellic Acid, RORA with Palmitic Acid, AR with Acoronene, AR with Epiacoronene, AR with 4,4'-Methylenediphenol, and HTR2A with Calycosin. Our molecular docking and molecular dynamics simulations suggest potential stable interactions between the formulation's active components and target proteins. These computational methods provide a preliminary theoretical framework that will guide our future experimental work. The study provides a scientific rationale for the use of traditional Chinese medicine in Tourette syndrome management and offers new insights for drug development.

Colorectal cancer (CRC) is one of the most common malignant cancers. Emodin is a lipophilic anthraquinone commonly found in medicinal herbs and known for its antitumor properties. However, its clinical utility has been hampered by low druggability. We designed and synthesized a new compound named Emodin succinimidyl ethyl ester (ESEE), which improves the bioavailability and preserves the original pharmacological effects of Emodin. In vitro, we have confirmed that ESEE induces apoptosis in colon cancer cells, suppresses cell proliferation, migration, and invasion, and inhibits the growth of subcutaneous transplantation tumors associated with colon cancer. And, in vivo, ESEE robustly inhibited tumor growth. Human Ether-a-go-go Related Gene (hERG) is aberrantly expressed in various cancer cells, where they play an important role in cancer progression. Focal adhesion kinase (FAK) is a tyrosine kinase overexpressed in cancer cells and plays an important role in the progression of tumors to a malignant phenotype. Mechanistically, the anti-CRC properties of ESEE are exerted through direct binding with hERG, which impedes the FAK/PI3K/AKT signaling axis-dependent apoptotic cascade.

Hepatitis B virus (HBV) is a DNA virus known to induce hepatitis and liver dysfunction, and is one of the main causes of liver cirrhosis and liver cancer. At present, there lacks a satisfactory optimal treatment plan for HBV in clinical practice, promoting the development of a novel Chinese formula, QingReJieDu Formula (QRJDF), as a potential solution.

This study aims to explore the underlying mechanisms of QRJDF in the treatment of Hepatitis B virus (HBV) through a combination of network pharmacology and experimental validation.

HepG2.2.15 cells were used to study the efficacy of QRJDF against HBV in vitro. Entecavir (ETV) was used as a positive control. Additionally, HBV transgenic mice served as subjects to study the in vivo efficacy of QRJDF against HBV, with serum and tissue samples analyzed post-euthanasia at 12 weeks to observe relevant indicators. UPLC-Q-TOF-MS technology was utilized to obtain the main ingredients in QRJDF. Network pharmacology was used to explore the potential ingredients and targets of QRJDF against HBV. Transcriptome sequencing was used to further explore the potential targets of QRJDF against HBV. Finally, integration of network pharmacology and transcriptomics results facilitated the screening of potential key targets and identification of potential pathways.

QRJDF demonstrated anti-HBV effects in HepG2.2.15 cells, compared to ETV control, QRJDF was more efficient in inhibiting HBV antigen levels, although it was less efficient in inhibiting HBV DNA level. In addition, the antiviral effect was verified in HBV transgenic mice. Network pharmacology results found three major active anti-HBV ingredients from QRJDF. Network pharmacology and transcriptomics revealed that QRJDF could act on the TGFβ1/Smad4 signaling pathway.

The study comprehensively evaluated the efficacy in vivo and in vitro, and fully confirmed that QRJDF was a potential therapeutic agent for HBV. In addition, the transcriptome technology was verified, and the key targets and approaches of QRJDF against hepatitis B were screened in combination with network pharmacology, which provided research ideas for the follow-up research of antiviral Chinese medicine.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the loss or low expression of estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2) and progesterone receptor (PR). Due to the lack of clear therapeutic targets, paclitaxel (PTX) is often used as a first-line standard chemotherapy drug for the treatment of high-risk and locally advanced TNBC. PTX is a diterpenoid alkaloid extracted and purified from Taxus plants, functioning as an anticancer agent by inducing and promoting tubulin polymerization, inhibiting spindle formation in cancer cells, and preventing mitosis. However, its clinical application is limited by low solubility and high toxicity. Nanodrug delivery system (NDDS) is one of the feasible methods to improve the water solubility of PTX and reduce side effects. In this review, we summarize the latest advancements in PTX-targeted NDDS, as well as its combination with other codelivery therapies for TNBC treatment. NDDS includes passive targeting, active targeting, stimuli-responsive, codelivery, and multimode strategies. These systems have good prospects in improving the bioavailability of PTX, enhancing tumor targeting, reducing toxicity, controlling drug release, and reverse tumor multidrug resistance (MDR). This review provides valuable insights into the clinical development and application of PTX-targeted NDDS in the treatment of TNBC.

Excessive nonesterified fatty acids (NEFA) impair cellular metabolism and will induce fatty liver formation in dairy cows during the periparturient. Baicalin, an active flavonoid, has great potential efficacy in alleviating lipid accumulation and ameliorating the development of fatty liver disease. Nevertheless, its mechanism remains unclear. Here, the potential mechanism of baicalin on system levels was explored using network pharmacology and in vitro experiments. Firstly, the target of baicalin and fatty liver disease was predicted, and then the protein-protein interaction (PPI) network was constructed. In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) (q-value) pathway enrichment is performed through the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server. Finally, the results of the network analysis of the in vitro treatment of bovine hepatocytes by NEFA were confirmed. The results showed that 33 relevant targets of baicalin in the treatment of liver fatty were predicted by network pharmacology, and the top 20 relevant pathways were extracted by KEGG database. Baicalin treatment can reduce triglyceride (TAG) content and lipid droplet accumulation in NEFA-treated bovine hepatocytes, and the mechanism is related to inhibiting lipid synthesis and promoting lipid oxidation. The alleviating effect of baicalin on fatty liver may be related to the up-regulation of solute vector family member 4 (SLC2A4), Down-regulated AKT serine/threonine kinase 1 (AKT1), Peroxisome proliferator-activated receptor gamma (PPARG), Epidermal growth factor receptor (EGFR), tumor necrosis factor (TNF), Interleukin 6 (IL-6) were associated. These results suggested that baicalin may modulate key inflammatory markers, and lipogenesis processes to prevent fatty liver development in dairy cows.

Metabolic reprogramming (MR) in cancer (CA) has been a focus of intense research in the recent two decades. This phenomenon has attracted great interest because it offers potential targets for cancer therapy. To capture the intellectual landscape of this field, we conducted a bibliometric analysis to assess the scientific output, major contributors, and trends in the MR/CA research.

We performed a systematic search using the Web of Science to retrieve articles published on MR of cancer from 2006 until 2023. The bibliometric tools such as Biblioshiny, VOSviewer, and Microsoft Excel were used to identify the most prolific authors, institutions, citation patterns, and keywords. We also used co-citation analysis to map the conceptual structure of the field and identify influential publications. Furthermore, we examined the literature by analyzing publication years, citations, and research impact factors.

A total of 4,465 publications about MR/CA were retrieved. Publications on MR/CA increased rapidly from 2006 to 2023. Frontiers in Oncology published the most papers, while Cell Metabolism had the most citations. Highly cited papers were mainly published in Cancer Cell, Nature, Cell, Science and Cell Metabolism. China and the United States led the way in publications and contributed the most to MR/CA research. The University of Texas System, Chinese Academy of Sciences, and Fudan University were the most productive institutions. The profitable authors were Deberardinis Ralph J and Chiarugi Paola. The current topics included MR in tumorigenesis and progression of CA, MR of tumor cells and tumor microenvironment, the effect of MR on the CA treatment, the underlying mechanisms of MR (such as gene regulation, epigenetics, extracellular vesicles, and gut microbiota), and the modulation of MR. Some topics such as tumor microenvironment, lipid MR, circular RNA, long noncoding RNA, exosome, prognostic model, and immunotherapy may be the focus of MR/CA research in the next few years.

This study evaluated the global scientific output in the field of MR/CA research, analyzing its quantitative characteristics. It identified some significant and distinguished papers and compiled information regarding the current status and evolving trends of MR/CA research.

In this manuscript, we comment on the article, which explores the anti-cancer effects of Calculus bovis (CB) in tumor biology. We highlight its potential, particularly in hepatocellular carcinoma (HCC), where it inhibits the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathways and induces apoptosis. CB contains compounds such as oleanolic acid and ursolic acid that target interleukin-6, mitogen-activated protein kinase 8, vascular endothelial growth factor, and caspase-3, offering anti-inflammatory and hepatoprotective benefits. The manuscript also discusses CB sativus (CBS), an artificial substitute, which has shown efficacy in reducing hepatic inflammation and oxidative stress in animal models. We emphasize the need for further research on the effects of CBS on the gut-liver axis and gut microbiota, and on targeting Wnt signaling and M2 tumor-associated macrophage as potential therapeutic strategies against HCC.

Liquiritigenin (LQ) is a monomeric compound found in licorice, a leguminous plant, and has been reported to exhibit antitumor effects in various lines of cancer cells. However, the underlying molecular mechanisms by which LQ exerts its antitumor effects remain largely unknown. In this study, the effects of LQ on the migration, invasion, and epithelial-mesenchymal transition (EMT) of prostate cancer (PCa) cells were investigated. We found that LQ effectively inhibited the migration and invasion of PCa cells in vitro, and this effect was further confirmed in xenograft lung metastasis models. In addition, LQ was found to activate endoplasmic reticulum stress (ER stress) in PCa cells. Further studies found that LQ upregulated the expression of inositol-requiring enzyme type 1α (IRE1). When IRE1 was knocked down, we observed a weakened inhibitory effect of LQ treatment on the migration and invasion of PCa cells. This observation suggests that LQ may inhibit the migration, invasion and EMT of PCa cells through activating the IRE1 branch of ER stress. In conclusion, our research may provide a novel therapeutic strategy for PCa.

Bufalin is a promising active ingredient in traditional Chinese medicine but has shown limited anticancer applications due to its toxicity. Here, we report BCNPs@gel, a bufalin-containing CaCO3 nanoparticle hydrogel, for enhancing cancer treatment through inducing cellular pyroptosis. Under the tumor microenvironment's low pH conditions, bufalin and Ca2+ are released from the delivery system. Bufalin serves as a direct anticancer drug and a Na+/K+-ATPase inhibitor by forcing the Na+/Ca2+ exchanger to reverse its function, which transfers Ca2+ into cytoplasm and ultimately causes Ca2+ overload-triggered pyroptosis. Meanwhile, we found that bufalin can upregulate PD-L1 in tumor cells. In combination with the PD-1 antibody, the delivery system showed a greater performance during the cancer treatment. BCNPs@gel enhances antitumor efficiency, reduces systemic side effects, extends antitumor mechanism of bufalin, and provides new strategies for inducing pyroptosis and calcium overload in cancer immunotherapy via Na+/K+-ATPase inhibitor. This work provides an application model for numerous other traditional Chinese medicine ingredients.

Ferroptosis, distinct from apoptosis, necrosis, and autophagy, is a unique type of cell death driven by iron-dependent phospholipid peroxidation. Since ferroptosis was defined in 2012, it has received widespread attention from researchers worldwide. From a biochemical perspective, the regulation of ferroptosis is strongly associated with cellular metabolism, primarily including iron metabolism, lipid metabolism, and redox metabolism. The distinctive regulatory mechanism of ferroptosis holds great potential for overcoming drug resistance-a major challenge in treating cancer. The considerable role of nanobiotechnology in disease treatment has been widely reported, but further and more systematic discussion on how nanobiotechnology enhances the therapeutic efficacy on ferroptosis-associated diseases still needs to be improved. Moreover, while the exciting therapeutic potential of ferroptosis in cancer has been relatively well summarized, its applications in other diseases, such as neurodegenerative diseases, cardiovascular and cerebrovascular diseases, and kidney disease, remain underreported. Consequently, it is necessary to fill these gaps to further complete the applications of nanobiotechnology in ferroptosis. In this review, we provide an extensive introduction to the background of ferroptosis and elaborate its regulatory network. Subsequently, we discuss the various advantages of combining nanobiotechnology with ferroptosis to enhance therapeutic efficacy and reduce the side effects of ferroptosis-associated diseases. Finally, we analyze and discuss the feasibility of nanobiotechnology and ferroptosis in improving clinical treatment outcomes based on clinical needs, as well as the current limitations and future directions of nanobiotechnology in the applications of ferroptosis, which will not only provide significant guidance for the clinical applications of ferroptosis and nanobiotechnology but also accelerate their clinical translations.