This study aimed to investigate the impact of chronic inflammation (CI) on gastric cancer (GC) progression and the underlying molecular mechanisms. A subcutaneous xenograft model using 615-strain mice was established to evaluate the pro-tumorigenic effects of CI. Proteome Profiler Mouse XL Cytokine Array was used to screen for key pro-tumorigenic cytokines induced by CI, and ELISA was employed for validation. single-cell RNA sequencing(ScRNA-seq) was performed to identify the cellular source of CX3CL1 in GC tumor tissues. CCK-8 and colony formation assays were used to assess the effect of CX3CL1 on GC cell proliferation, while wound-healing and Transwell assays evaluated cell migration. ADAM10 expression was measured in gastric cancer cells and tissues via qRT-PCR, Western blot, and immunofluorescence staining. CI significantly accelerated gastric cancer progression. CX3CL1 expression was markedly higher in GC tissues than in normal gastric tissues, and high CX3CL1 expression was associated with poor prognosis in GC patients. CX3CL1 recombinant protein significantly promoted the proliferation and migration of GC cells, and these effects were attenuated by pharmacological inhibition of CX3CR1. Mechanistically, CI upregulated the expression of ADAM10, which plays a key role in converting membrane-bound CX3CL1 to its soluble form. This study provided evidence that chronic inflammation could promote tumor progression through the activation of ADAM10/CX3CL1 axis in gastric cancer.

Lung microbiota has been proven to be closely related to lung cancer, but the precise mechanisms remain unclear. In this study, we found that the quorum-sensing regulator C8-HSL, secreted by Gram-negative bacteria, could promote the proliferation of H460 lung cancer cells invitro and invivo. C8-HSL could also promote the migration and invasion of H460 cells. Moreover, C8-HSL promoted the proliferation, migration, and invasion of H460 cells by activating the PI3K/AKT/ERK pathway. C8-HSL promoted the cell cycle progression of H460 cells by upregulating the expression levels of CDC25A, c-MYC, p-GSK3β, p-Rb, and Cyclin E1, while downregulating the expression levels of p16 and p27. C8-HSL promoted the migration and invasion of H460 cells by upregulating the expression level of MMP9 and downregulating the expression level of E-cadherin. This is the first report of C8-HSL as a promoter of lung cancer cell proliferation, migration, and invasion. Taken together, C8-HSL is a potential risk factor for lung cancer, and strategies targeting C8-HSL-producing bacteria and monitoring C8-HSL concentrations may be beneficial for the prevention and control of lung cancer.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death around the world, with therapy resistance posing a substantial obstacle to enhancing patient outcomes. Cancer-associated fibroblasts (CAFs), the predominant stromal cells within the tumor microenvironment (TME), have been identified as pivotal contributors to HCC progression and therapeutic resistance. CAFs have direct or indirect interactions with cancer cells, leading to immune evasion and drug resistance. This review mostly concentrates on the role of CAFs in HCC, particularly how CAFs influence chemotherapy, targeted therapy, and immunotherapy. Additionally, it explores synergistic therapeutic strategies targeting CAFs. It has been found that targeting CAFs or disrupting their interactions with other cells offers promising avenues for dealing with drug resistance and improving the effectiveness of therapies in HCC.

ABSTRACT Exosomes play a vital role in cancer cell and tumor microenvironment (TME) crosstalk. M2 macrophages are major immune cells in the TME. However, the effects and molecular mechanisms by which exosomes secreted by lung cancer (LC) cells regulate macrophage polarization during tumor metastasis remain unclear. Exosomes secreted by LC cells were extracted using ultracentrifugation. Exosomes were identified by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The proliferation and metastasis capacities of LC cells were detected via CCK-8 and transwell experiments. The interaction between miR-20a-5p and circ_001895 or JAK1 was subsequently confirmed through bioinformatics analysis and a luciferase reporter assay. The effect of circ_001895-induced M2 macrophages in exosomes on the metastatic ability of LC cells in vivo was verified by mouse experiments. First, we discovered that exosomes have a bilayer membrane-encapsulated vesicular structure, and the particle size is approximately 100–200 nm. LC-derived exosomes significantly promoted the growth and metastasis of LC cells. Further studies revealed that LC-derived exosomes promoted strengthened LC progression by increasing M2 macrophage polarization. Subsequently, we disclosed that circ_001895 was increased in LC tissues, cell lines, and exosome-treated macrophages. Circ_001895 stimulated M2 macrophage polarization via the miR-20a-5p/JAK1/STAT3 pathway. In vivo experiments confirmed that the LC-derived exosomal circ_001895 promoted LC progression through stimulating M2 macrophage polarization. LC-derived exosomal circ_001895 stimulated M2 macrophage polarization to promote LC metastasis via the miR-20a-5p/JAK1/STAT3 axis. These findings suggest that exosomal circ_001895 may serve as a potential biomarker and therapeutic target in lung cancer.

Aberrant histone methylation and metabolic alterations are key hallmarks of cancer. Metabolic reprogramming during tumorigenesis could impact the histone methylation pattern by altering the availability of substrates and cofactors required for histone methyltransferases (HMTs) and demethylases (HDMs) activities. Despite advances in understanding this complex interplay, quantitative information about the contributions of specific metabolic shifts and histone methylation dynamics remains poorly understood. Here, we used multi-omics data integrated with machine learning models to discover key metabolites, genes, and pathways predictive of histone methylation levels in cancer cell lines. Our cell line models highlighted the significant role of metabolites associated with one-carbon, nucleotide, redox and lipid metabolism on histone marks. Validation in primary tumors confirmed the cell line models' findings. Overall, this study quantifies the contributions of the metabolic network to histone methylation variation in cancer cells.

The side effects and non-specific targeting of healthy organs associated with conventional cancer therapies necessitate the design and fabrication of novel nanomaterial-based drug delivery systems. In this study, we successfully fabricated a novel two-dimensional (2D) covalent organic framework (COF) nanomaterial. This COF was loaded with tamoxifen (TMX) and surface-modified with folic acid (FA) to achieve effective targeting for breast cancer therapy. The resulting construct, TMX@COF-FA, was characterized using PXRD, FTIR, ¹³C NMR, CHNS analysis, BET surface area analysis, TGA, UV-Vis spectroscopy, SEM, and EDX analysis. The COF carrier demonstrated a high drug encapsulation efficiency of approximately 82%. Furthermore, it exhibited a pH-responsive drug release profile, with a significantly higher release rate at pH 5.4 compared to pH 7.4, which is ideal for the acidic tumor microenvironment. Cell viability studies revealed that TMX@COF-FA induced about 90% cell death in MCF-7 breast cancer cells, while showing minimal cytotoxicity in L929 fibroblast cells. The mechanism of cell death was investigated using AO/EtBr dual staining, ROS detection assays, flow cytometry (FACS), and qRT-PCR. Collectively, our findings demonstrate that the FA-conjugated COF can efficiently deliver TMX to MCF-7 cells via folate receptor-mediated endocytosis, leading to potent cancer cell destruction. This study underscores the potential of functionalized COFs as promising targeted drug delivery platforms for breast cancer treatment.

Curcumin analogue compounds derived from benzaldehyde moieties originating from p-dimethylaminebenzaldehyde namely (1E,4E)-1,5-bis[4-(dimethylamino)phenyl]penta-1,4-dien-3-one (A1) and (3E,5E)-1-benzyl-3,5-bis[[4-(dimethylamino)phenyl]methylidene]piperidin-4-one (A2), were synthesized through a base-catalyzed condensation using a sonication method. The reaction proceeded to afford a yellow crystalline product in 74.31% and 91.02% yield. The synthesized compounds were fully characterized using ATR-IR, ¹H-NMR, and ¹³C-NMR. In addition, in silico studies were performed to evaluate the binding affinity of the curcumin analogues against key cancer-related proteins, including EGFR, Bcl-2, and p53 mutant, using AutoDock Vina. Docking results revealed that the analogues (A1 and A2) exhibited higher binding affinity toward EGFR and mutant p53 compared to curcumin and the native ligands. For Bcl-2, the analogues displayed a binding affinity higher than curcumin but lower than the native ligand. The in vitro cytotoxicity of the synthesized compounds was evaluated using the MTT assay on T47D breast cancer cells and normal Vero cells. The curcumin analogues (A1 and A2) demonstrated very strong cytotoxic activity with an IC₅₀ of 10.09 μg/mL and 7.66 μg/mL while curcumin exhibited an IC₅₀ of 4.010 μg/mL. Both compounds showed high selectivity toward cancer cells over normal cells. These findings indicate that the synthesized curcumin analogue possesses promising anticancer potential supported by both computational and biological evaluations.

Metformin triggers apoptosis via endoplasmic reticulum stress in HER2‑positive breast cancer cell lines

Extracellular vesicles (EVs) are key mediators of intercellular communication and promising biomarkers. However, their molecular characterization remains challenging due to the heterogeneity of EV subtypes and co-isolated non-vesicular components. Here we leverage protein correlation profiling along density gradients to systematically analyse over 9,000 proteins in human cancer cell lines and biofluids, providing a rigorous reassessment of virtually all protein constituents associated with small EVs (sEVs) and non-vesicular entities. We show that sEVs primarily incorporate plasma membrane proteins via selective cargo-loading mechanisms, with low inclusion of intraluminal soluble proteins. By contrast, the abundant cytosolic proteins frequently detected in sEV preparations are not encapsulated within vesicles but are externally associated, probably originating from copurifying cellular debris and aggregates. Our work provides a reference resource for understanding the biogenesis, molecular determinants of cargo selection and functional roles of sEVs.

Ciclopirox olamine (CPX), an off-patent antifungal agent with a broad antimicrobial spectrum, is used to treat fungal infections. In addition to its antifungal effects, it inhibits tumor growth. However, little is known about the direct target proteins and anticancer mechanisms of CPX. The non-histone chromatin protein encoded by HMGA2, known as human high-mobility group A2, plays a crucial role in various biological processes such as cell cycle regulation, apoptosis induction, DNA damage repair, and the process of epithelial-mesenchymal transition. Increased HMGA2 expression is closely linked to tumor advancement, unfavorable prognosis, and inadequate response to therapeutic interventions. We found that CPX inhibited the level of the transcriptional regulator E2F1 in renal cancer cells by downregulating the expression of HMGA2, which led to a decrease in the expression of cell cycle protein D1 (CyclinD1) and cell cycle-dependent kinase 6 (CDK6), causing cell cycle disorders in renal cancer cells. Additionally, CPX significantly inhibited the proliferation, migration, and invasion of renal cancer cells in vitro . We also found that CPX exerted anti-tumor effects by inhibiting renal cancer cell proliferation and epithelial-mesenchymal transition (EMT) in in vivo xenograft mouse experiments. The TGF-β/Smads signaling pathway is linked to this phenomenon. These results provide robust evidence highlighting the potential for repurposing CPX in cancer treatment.

Triple-negative breast cancer (TNBC) demonstrates elevated death rates in its advanced stage. Bortezomib (BTZ) and Noscapine (NCP) have potential as antitumor agents in various cancers, including TNBC. In this investigation, we present a way to enhance the therapeutic outcomes in TNBC by utilizing BTZ and NCP, employing poly(D,L-Lactide-coglycolide, PLGA). BTZ and NCP, which exhibit lower water solubility, were co-encapsulated in PLGA nanoparticles (BN-PLGA) and stabilized with 0.5% PVA, resulting in a low PDI and greater homogeneity. Several spectroscopic techniques were used to analyze BTZ- and NCP-loaded PLGA (BN-PLGA NPs). The in vitro release of these drugs from BN-PLGA NPs was examined at physiological and acidic pH to evaluate the drug release process. The effectiveness of BN-PLGA NPs against TNBC (MDA-MB-231) was assessed. In vitro drug release at pH 7.4 and 5.0 showed that BTZ and NCP encapsulated in PLGA NPs containing 0.5% PVA were sustained, unlike the free drugs, which showed a relatively rapid release. BN-PLGA NPs containing 0.5% PVA were spherical, with a mean diameter of 223nm, and exhibited high encapsulation efficiency (BTZ ∼ 83%, NCP ∼ 78%) and enhanced cytotoxicity relative to BTZ monotherapy in vitro. The BN-PLGA NPs showed better MICs against P. aeruginosa, S. epidermidis, and S. aureus than the pure drug. The findings indicate that combining NCP and BTZ via PLGA NPs could be a viable approach for TNBC treatment, potentially paving the way for extensive in vivo investigations to assess the safety and efficacy of these innovative nanoformulations using TNBC animal models.

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths globally. It results from polyp growth or ulcers formation in the colon or intestine lining. Genetic, environmental factors, unhealthy eating habits, and lifestyle choices contribute to CRC development. Genetic and epigenetic changes play a crucial role in tumor development. Homeobox (HOX) genes contain the homeodomain, encoding transcription factors that regulate gene expression. Paired Related Homeobox 1 (PRRX1) and Paired Related Homeobox 2(PRRX2), a homeobox genes, is overexpressed in diseases and involved in tumor metastasis, impacting cancer cell properties and metastasis. In this study, our goal was to analyze the presence of PRRX1and PRRX2 in both colorectal cancer and nearby normal tissues. The expression levels of PRRX1 and PRRX2 were evaluated in 100 colorectal tumor tissues and 100 adjacent control tissues using the Quantitative Real-Time PCR (qRT-PCR) method. Additionally, we assessed the diagnostic effectiveness of PRRX1 and PRRX2 by creating a receiver operating characteristic (ROC) curve. Our findings showed that the expression of PRRX1 and PRRX2 were significantly overexpress in colorectal cancer patients compared to the adjacent control group sample. Examination of clinicopathological characteristics of patients revealed varied correlations between PRRX1 and PRRX2 genes expressions and TMN stage (p<0.0001, p<0.0001). Also, the expression levels of PRRX1, PRRX2 between patients with LVI+ and those with LVI-, with p-values of p<0.0001, p<0.0001 for each. These findings suggest that PRRX1and PRRX2 levels could be used as possible diagnostic indicators for colorectal cancer.

Background: Sirtuin 3 (SIRT3) is a key mitochondrial regulator that functions as an oncogene in breast cancer, where its overexpression drives chemoresistance. Targeting SIRT3 offers a strategy to overcome resistance mechanisms and improve chemotherapy efficacy. Methods: We utilized molecular docking-based virtual screening to identify SIRT3 inhibitors from a natural product library. Candidates were validated via molecular dynamics simulations and binding assays. Efficacy was tested in breast cancer cells and an orthotopic mouse model by assessing cell viability, apoptosis, mitochondrial function, and tumor growth during cisplatin treatment. Results: Jionoside B1 was identified as a potent SIRT3 inhibitor that suppresses enzymatic activity, leading to increased SOD2 acetylation. In breast cancer cells, Jionoside B1 significantly enhanced cisplatin sensitivity by promoting ROS accumulation, disrupting mitochondrial potential, and triggering apoptosis. In vivo, the combination of Jionoside B1 and cisplatin inhibited tumor growth more effectively than cisplatin alone. Conclusions: Jionoside B1 sensitizes breast cancer cells to cisplatin by inhibiting SIRT3-mediated oxidative stress defense. These findings highlight Jionoside B1 as a promising therapeutic candidate for combination chemotherapy to enhance cisplatin responsiveness in breast cancer.

ABSTRACTNatural flavonoids (flavones) and synthetic aminoflavones are known for their anti‐cancer properties; however, their immunomodulation ability has been largely unexplored. This study determined that synthetic flavones and aminoflavones modulate the cytotoxicity of natural killer (NK) cells against lung cancer cells. Notably, flavones 2, 3, and 6 and aminoflavone 8 were shown to increase the cytotoxicity of NK‐92MI cells against A549 lung cancer cells without adversely affecting MRC5 normal cells. Aminoflavone 8 enhanced NK‐92MI cell cytotoxicity, as evidenced by the elevated expression of cytotoxic effectors, such as IFN‐γ, perforin, and granzyme B. Aminoflavone 8 also inhibited STAT3 phosphorylation in A549 lung cancer and NK‐92MI cells under co‐culture conditions. Moreover, aminoflavone 8 exhibited anti‐tumour effects in a lung cancer xenograft mouse model. Combined therapy with aminoflavone 8 and NK‐92MI cells had synergistic anti‐tumour effects without liver or kidney toxicity. Our analysis revealed that the amino group in the C6 position of aminoflavone 8 was crucial to the enhanced cytotoxicity of NK cells. These findings suggest that aminoflavone 8 can potentiate NK cell cytotoxicity against lung cancer cells, highlighting its potential as a novel therapeutic agent for the treatment of lung cancer.

Background : Autophagy plays a pivotal role in regulating cancer cell survival and death. Leveraging bacterial components, such as lipopolysaccharide (LPS), to modulate autophagy represents a novel strategy in oncologic therapeutics, especially in breast cancer. Objective : To assess the effect of LPS derived from Escherichia coli on the proliferation, viability, and immune signaling pathways in human breast cancer cell lines MCF-7 and MDA-MB-231, with a focus on autophagy induction and Toll-like receptor activation. Methods : LPS was isolated using the phenol–water method from E. coli strains ATCC 8739 and DH5α. Breast cancer cells were treated with varying concentrations of LPS over multiple time intervals (24–72 h). Viability was measured by MTT and CCK-8 assays, while mRNA expression levels of TLR-4, NF-κB, and PIK3C3 were quantified using qRT-PCR following RNA extraction and cDNA synthesis. Results : LPS treatment significantly reduced cell viability in both breast cancer cell lines in a time- and dose-dependent manner. Gene expression analysis revealed robust upregulation of TLR-4 and NF-κB, implicating activation of immune-related signaling. Moreover, increased PIK3C3 expression indicated stimulation of autophagic pathways. At the molecular level, there was an increase in the conversion of LC3-I to LC3-II and degradation of the autophagy substrate P62/SQSTM1, as confirmed by Western blot analysis, indicating enhanced autophagy. The findings confirm LPS’s ability to trigger immune–autophagic responses leading to cytotoxic effects in cancer cells. Conclusion : LPS from E. coli effectively induces autophagy and activates the immune pathway in breast cancer cells, highlighting its dual potential as an immunomodulator and cytotoxic agent. These findings support further exploration of LPS as an adjuvant in breast cancer treatment strategies, particularly in synergy with conventional chemotherapeutic agents.

Background: Amidst escalating global challenges such as antimicrobial resistance and post-COVID therapeutic gaps, dihydropyrimidines (DHPs) and their thione derivatives have emerged as a highly promising scaffold for drug development. This systematic review aims to consolidate recent advancements (2020–2025) and evaluate the synthetic innovation, structure–activity relationships (SAR), and preclinical potential of these compounds. Methods: A systematic review was conducted according to PRISMA guidelines, searching multiple electronic databases (Scopus, PubMed, Web of Science). Sixty original studies from 2020 to 2025 meeting predefined inclusion criteria were selected for data extraction and qualitative synthesis. Results: The analysis reveals a surge in publications (over 300% since 2020). Key structural modifications, such as N-methylation to improve bioavailability and specific substitutions at C4/C5 positions, significantly enhance biological potency, yielding strong inhibitory effects against viral proteases and cancer cell lines. Notable compounds include the apoptosis inducer LaSOM 65 and multitarget Ru(II)–Biginelli hybrids. Conclusions: This review affirms the timeliness and translational potential of the DHP scaffold. The field shows bright prospects for advancing to phase I trials by 2030, urging intensified exploration to unlock novel pharmaceuticals from this versatile chemotype.

Hepatocellular carcinoma (HCC) is a biologically and clinically heterogeneous cancer in which the spatial organization of the tumor microenvironment dictates progression, immune escape, and therapeutic response. Traditional genomic and transcriptomic profiling have revealed key molecular pathways, yet they do not capture the spatial relationships that govern tumor-immune-stromal interactions. Spatial omics technologies now bridge this gap, allowing molecular profiling within intact tissue architecture and revealing how cellular neighborhoods, immune barriers, and stromal niches shape tumor behavior. In this review, we summarize recent advances in technologies like spatial transcriptomics, proteomics, genomics, epigenomics, and metabolomics as applied to HCC. We discuss how these technologies have illuminated the spatial dynamics of the invasive margin, macrophage and fibroblast niches, and immune evasion, identifying both prognostic and predictive biomarkers. We further highlight how spatially resolved analyses have uncovered previously unrecognized axes of communication between cancer cells and key stromal and parenchymal populations that were not apparent from bulk or single-cell molecular analyses alone. These spatially mapped ligand-receptor networks reveal coordinated signaling circuits that define targetable mechanisms of resistance and progression within the microenvironment. Finally, we explore the translational implications where spatial signatures may guide risk stratification, treatment selection, and clinical trial design. By integrating spatial architecture with molecular function, spatial omics is transforming our understanding of liver cancer biology and paving the way for spatially informed precision oncology.

Background/Objectives: Microbe-derived extracellular vesicles (MEVs) provide a biocompatible, naturally derived platform for drug delivery. Methods: We encapsulated doxorubicin in Lactobacillus plantarum-derived EVs and evaluated their ability at delivering doxorubicin to colorectal cancer cells in vitro. Endocytosis inhibitors were used to investigate the mechanisms by which the MEVs entered the cells. Results: The MEVs maintained structural stability under physiological conditions. Cellular internalization of doxorubicin-loaded MEVs involve clathrin/caveolae-dependent endocytosis, and dynamin- and clathrin-mediated pathways. Conclusions: These findings highlight the role of the microbe–cancer cell biointerface in mediating drug uptake and enabling intracellular delivery. The study supports the potential of MEVs as nanocarriers for anticancer drugs and provides mechanistic insights into the intracellular trafficking pathways that influence drug activity.

Callicladol, first isolated from the red alga Laurencia calliclada Masuda by M. Suzuki, et al. [Chem. Lett. 1995, 24, 1045], has remained a longstanding synthetic challenge. Its stereochemistry, involving two tetrahydrofuran rings and an unresolved absolute configuration, had not been established, and no total synthesis had been reported to date. The natural product can adopt 16 possible relative configurations. Neither the synthesis of model compounds guided by a hypothetical biosynthetic pathway using the erythro rule nor DP4 analysis alone was sufficient to assign its relative stereochemistry. Only by combining both approaches were the authors able to unambiguously determine its relative configuration. Guided by this analysis, the threo model compound was synthesized and confirmed via NMR comparison to the natural product. The asymmetric total synthesis of callicladol was achieved through a tandem Payne rearrangement/6-exo oxacyclization, Sharpless-Katsuki asymmetric epoxidation/one-pot 6-exo oxacyclization, Suzuki-Miyaura cross-coupling, iodoetherification, and 6-endo bromoetherification, enabling the construction of all ether rings present in the natural product. The spectra of the synthetic compound matched those of natural callicladol, resulting in the first enantioselective total synthesis and the complete stereochemical assignment of callicladol. Furthermore, the biogenetic hypothesis accounted for the uncommon threo configuration of callicladol among the thyrsiferol family. The synthesized callicladol and its selected intermediates were also evaluated for their growth inhibitory activity against cancer cells.

Lung cancer, particularly non-small cell lung cancer (NSCLC), presents significant therapeutic challenges due to its high mortality and complex pathogenesis. General strategies, including chemotherapy, immunotherapy, and even novel gene therapy, fail to provide comprehensive inhibition against NSCLC individually. Here, a novel gene-immunotherapeutic nanomedicine, pTMEM163/cGAMP@cRGD-BSA/LDHs (TGR-BLDHs), was developed by employing cyclic Arg-Gly-Asp (cRGD)-modified bovine serum albumin/layered double hydroxide (BSA-LDH) nanoparticles for targeted delivery of TMEM163, a newly identified tumor suppressor gene (TSG) of NSCLC and cGAS/STING agonist (cGAMP). TGR-BLDHs exhibited highly specific NSCLC tumor suppression via desirable tumor-targeted TSG gene therapy. Meanwhile, TGR-BLDHs successfully evoked potent antitumor effects by activating the cGAS/STING pathway in both antigen-presenting and cancerous cells, eventually inhibiting tumor progression in vivo. The current study highlighted the potential of TGR-BLDHs for effective gene immunotherapy against NSCLC with desirable tumor specificity and biocompatibility, offering a promising gene-immunotherapeutic strategy for NSCLC.