Human Cancer Research Articles

Gliomas are central nervous system primary tumors that are distinguished by heterogeneity, broad-based infiltration, and metabolic reprogramming that sustains proliferation, invasion, and therapy refractoriness. Oxidative stress—a state of imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense—and disturbed iron metabolism are central drivers of glioma biology. The aim of this study was to evaluate ROS production, sulfane sulfur levels, the expression of proteins with antioxidant properties, such as L-cysteine-metabolizing enzymes (cystathionine β-synthase, CBS; cysteine dioxygenase 1, CDO1; cystathionine γ-lyase, CTH; 3-mercaptopyruvate sulfurtransferase, MPST; thiosulfate sulfurtransferase, TST) and non-enzymatic proteins (p53; transferrin receptor 1, TfR1), in human brain cancer cells differing in malignancy: 1321N1 astrocytoma and T98G glioblastoma. Western blotting analysis demonstrated that the expression of CBS, CDO1, and TfR1 was significantly increased in T98G cells, while CTH, MPST, TST, and p53 were comparably expressed in both cell lines. Quantitative assays revealed that T98G cells harbored significantly higher sulfane sulfur levels and higher numbers of ROS-positive cells compared to 1321N1 cells. Our results suggest that glioblastoma but not astrocytoma cells adapt sulfur and iron metabolism to provide proliferation capacity against chronic oxidative stress. It seems that CBS as well as CDO1 may significantly increase the antioxidant potential of T98G cells. In summary, this study suggests a differing metabolic vulnerability identifiable only in high-grade glioma cells and provides a potential novel molecular target for therapy.

Arginine, a critical amino acid for protein structure and function, is involved in enzyme catalysis and macromolecular interactions. However, selectively targeting its reactive guanidine group has been challenging. Here, we utilized a probe, AP-1, based on phenylglyoxal, which demonstrated remarkable chemical selectivity and reactivity toward arginine residues. Using activity-based protein profiling (ABPP), we explored the human proteome across four cancer cell lines, obtaining quantitative data for approximately 17000 arginine residues. This analysis led to the identification of several previously unreported hyperreactive arginine residues, including R43 of PKM, R171 of LDHA, R172 of LDHB, R341 of CKB, R168 of EIF4A1, and R118 of FUBP1, which are crucial for protein function. Notably, the mutation of CKB's R341 inhibited cell proliferation and migration by downregulating energy supply. We also introduced ArGO-LDHA-1, a covalent inhibitor targeting LDHA's hyperreactive arginine residues, showing potential to enhance chemotherapy efficacy. This work highlights the biological significance of arginine residues and provides a platform for large-scale profiling of arginine reactivity.

Background/Objectives: Glioblastoma (GBM) is a fatal tumor in the central nervous system (CNS) with a poor prognosis. Preventing tumors from post-surgical recurrence is a significant clinical challenge, since current methods deliver chemotherapeutic agents in a rapid manner and are not effective against the residual tumor cells. To address these limitations, we develop a blue light-crosslinking hydrogel which can be rapidly gelled in situ and tightly adhere on the tissues for controlled chemotherapy, radiotherapy, and enhanced laser interstitial thermal therapy (LITT) to inhibit residual tumor cells from post-surgical recurrence. Methods: We utilize gelatin-MA based hydrogel with crosslinker VA-086 as hydrogel scaffold to encapsulate small-molecule drugs (Epirubicin and Cisplatin) and LITT agent polypyrrole-coated graphine oxide (PPy@GO). The mixture can form into hydrogel in situ by blue light irradiation and performed chemo-LITT and radio therapy simultaneously. Then we determine the prevailing factors that affect efficient encapsulation of therapeutic agents within hydrogels, efficiency of gelation, LITT enhancement, and drug release. Then evaluate efficiency in human cancer cells and an in vivo tumor model. Results: Our results demonstrate that 18 wt% Gelatin MA formulation achieved >95% gelation within 2 min, with drug-loaded gels forming within 5 min. The gelation can perform both in vitro and in vivo without affect the drug efficiency. This multi-treatment system can effectively prevent tumor recurrence and significantly prolong the medium survival of glioma-bearing (MBR-614 or U87-MGFL) mice to above 65 days compared with the control group (36 days). Conclusions: The results demonstrated promising effect of this system as a multi-therapeutic platform which combined chemo-LITT and RT. This synergistic strategy presents a new approach to the development of a local drug delivery system for the prevention of brain tumor recurrence.

Heterogeneous nuclear ribonucleoprotein M (hnRNPM) is an RNA-binding protein that is aberrantly expressed in tumorigenesis. However, the alternative splicing regulation by hnRNPM in human colorectal cancer (CRC) remain unclear. Herein, we observed that hnRNPM was highly expressed in CRC tissues. The knockdown of hnRNPM inhibited the proliferation of colon cancer cells both in vivo and in vitro. Using RNA-seq, we screened and identified several alternative splicing events regulated by hnRNPM. Knockdown of PLEKHB2-S splice isoform could reduce the growth of colon cancer cells in vitro and in vivo, predicting its role in malignant proliferation of colon cancer cells. Mechanically, the minigene reporter assay indicated the predominant regulatory roles of hnRNPM in PLEKHB2 splicing. The in vivo crosslinking immunoprecipitation (CLIP) assay demonstrated the direct binding of the RNA recognition motif RRM2 of hnRNPM protein to exon 9 of PLEKHB2 pre-mRNA. HnRNPM facilitated the skipping of alternative exon 8 in PLEKHB2 by binding to the constitutive exon 9. Furthermore, we developed cationic microbubbles shRNA/CMBs and transferred to colon cancer cells via ultrasound-targeted microbubble disruption (UTMD). The size and zeta potentials of CMBs and shRNA-CMBs were measured and the optimal concentration range of shRNA/CMBs were screened with low cytotoxicity. The introduction of sh-hnRNPM/CMBs or sh-PLEKHB2-S/CMBs suppressed the proliferation of colon cancer cells in vitro and in vivo. Collectively, our findings identify that hnRNPM dysregulates colorectal carcinoma proliferation at the molecular level of splicing regulation and predicate sh-hnRNPM/CMBs and its splicing target sh-PLEKHB2-S/CMBs as promising therapeutic drugs and innovative strategies for treating colorectal cancer. Schematic diagram of the functions of UTMD mediated sh-hnRNPM/CMBs in colorectal cancer and emerging mechanism by which hnRNPM promotes the malignant proliferation of CRC by regulating the alternative splicing of PLEKHB2 pre-mRNA. The picture was created with BioRender.com.

Thyroid carcinomas are phenotypically heterogeneous malignancies. Advances in molecular and cellular technologies have revealed genetic, epigenetic, and nongenetic factors underlying this heterogeneity. Our study aimed to assess the impact of single and combined treatments with anticancer agents (Carboplatin, Doxorubicin, Paclitaxel, Avastin), natural compounds (Quercetin), and epigenetic modulators (suberoylanilide hydroxamic acid and 5-Azacytidine) on the expression of long noncoding RNAs, methylation regulators, and functional features in the human thyroid cancer cell line K1. Methods: Treated and untreated K1 cells were used throughout experiments to evaluate the drug-induced cytotoxicity, apoptosis, cell cycle distribution, cytokine release, gene expression, and global DNA methylation levels. Results: Some single- and combined-drug treatments modulated both cell cycle progression and apoptotic events, demonstrating anti-tumor activity of the tested compounds. Gene expression analysis showed treatment-specific regulation of target genes and lncRNAs, including both upregulation and downregulation across different drug combinations. All treatments resulted in increased global DNA methylation levels compared to the untreated controls. Several combinations significantly upregulated DNMT1 and DNMT3B, while concomitantly decreased EZH2 levels. Conclusions: These coordinated epigenetic changes highlight the therapeutic potential of combining epigenetic modulators with chemotherapeutic agents, suggesting a strategy to prevent or reverse treatment resistance and improve outcomes in thyroid cancer patients.

β3-adrenergic receptors (β3-ARs) are increasingly recognized as modulators of tumor progression and treatment resistance across multiple cancer types. SR59230A, a β3-AR antagonist, has shown preclinical antitumor activity through mechanisms involving mitochondrial reactivation, reactive oxygen species (ROS) production, and antiangiogenic effects. Based on this premise, this study aimed to investigate the in vitro synergistic effects of SR59230A combined with standard chemotherapeutics or targeted therapies in various human cancer cell lines (glioblastoma, melanoma, triple-negative breast cancer, and anaplastic thyroid carcinoma) and endothelial cells (HUVECs). Cells were treated with SR59230A alone or in fixed-ratio combinations with temozolomide, paclitaxel, vemurafenib, lenvatinib, or sorafenib. Drug interactions were quantified using the Chou-Talalay method and validated with the Loewe additivity model. SR59230A exhibited dose-dependent antiproliferative activity, particularly in HUVECs and thyroid carcinoma cells. Synergistic effects were observed in all models, with the strongest synergy in A-2058 melanoma cells (SR59230A + vemurafenib), MDA-MB-231 breast cancer and 8505C thyroid carcinoma cells (SR59230A + paclitaxel), U-87 glioblastoma cells (SR59230A + temozolomide), and HUVECs (SR59230A + lenvatinib or sorafenib). Dose reduction index (DRI) values confirmed the potential to lower cytotoxic drug doses while preserving efficacy. These findings suggest that SR59230A may enhance the efficacy of conventional and targeted anticancer agents through multimodal mechanisms. The consistent synergistic effects across diverse tumor types support further investigation into the role of SR59230A, including its effects on β3-AR, as a promising strategy to overcome resistance and optimize cancer therapy.

N-vinylindoles have attracted attention for their promising role in medicinal chemistry. Therefore, developing new synthetic methods that enable access to diverse functionalized N-vinylindoles with potential pharmacological properties is highly valuable. 1-[2-aryl-1-(4,5-dihydro-1H-imidazol-2-yl)vinyl]-1H-indoles 2a-i were prepared via Knoevenagel condensation promoted by 1H-benzotriazole, and characterized by IR, NMR, and MS spectroscopic data as well as a single-crystal X-ray diffraction-based study of the representative derivative 2g. The obtained compounds 2a-i were screened for their cytotoxic potency against human cancer cell lines (HeLa, SKOV-3, AGS) and non-cancerous cell line (HaCaT) using the MTT assay. Additional apoptosis analysis and cell cycle assay on SKOV-3 cells were conducted. Their antimicrobial activity was determined using reference strains of S. aureus, E. coli, C. albicans, and C. glabrata. The potent inhibitory activity against AGE2-BSA/sRAGE interaction of selected N-vinylindoles 2b, 2d-f, and 2h-i was evaluated by ELISA assay. A facile approach has been developed for the synthesis of a novel class of N-vinylindoles. The preliminary structure–activity considerations indicated that the presence of substituents R, such as 4-bromophenyl (compound 2f) or 2-naphthyl (compound 2i) is optimal for anticancer activity and the AGE2-BSA/sRAGE interaction inhibition. The most prominent (Z)-1-[1-(4,5-dihydro-1H-imidazol-2-yl)-2-(naphthalen-2-yl)vinyl]-1H-indole (2i) was found to strongly arrest cell cycle in the SKOV-3 cell line in the subG0 phase, inducing apoptosis. Notably, derivative 2i also exhibited the highest activity against S. aureus and C. albicans strains within the tested series. These findings highlight the substantial potential of N-vinylindole derivative 2i as a lead compound for the development of anticancer drugs with additional inhibitory activity on the AGE/RAGE interaction.

Cancer is characterized by uncontrolled cell proliferation and the evasion of programmed cell death. The dysregulation of the cell cycle is a fundamental hallmark of nearly all human cancers, making its core machinery an attractive target for therapeutic intervention. Concurrently, the ability of cancer cells to resist apoptotic signals is a primary mechanism of tumorigenesis and therapy resistance. This has spurred the search for agents that can simultaneously reinstate cell cycle control and trigger robust cell death pathways. Natural products, particularly polyphenols, have emerged as a promising source. Pyrogallol (1,2,3-trihydroxybenzene), a simple phenolic compound found in numerous plants, has demonstrated potent anticancer activities across a wide range of malignancies. This review synthesizes the current understanding of pyrogallol's mechanism of action, rooted in its pro-oxidant nature. Pyrogallol autoxidation generates a massive burst of intracellular Reactive Oxygen Species (ROS) and causes a concomitant depletion of Glutathione (GSH), creating severe oxidative stress. This oxidative assault is particularly effective against cancer cells, which often have a compromised redox balance, rendering them more vulnerable than their normal counterparts. This ROS/GSH imbalance acts as a master signal to initiate a multifaceted attack on cancer cells by comprehensively rewiring cellular signaling, leading to the inhibition of critical pro-survival pathways (e.g., PI3K/Akt) and the activation of stress-responsive kinase pathways (e.g., JNK, p38). These signaling alterations converge to induce robust cell cycle arrest, primarily at the G2/M transition, and trigger the intrinsic mitochondrial pathway of apoptosis, marked by mitochondrial membrane depolarization, modulation of Bcl-2 family proteins, and caspase activation. This review provides a cohesive model of pyrogallol's action, highlighting its potential as a lead compound for developing novel oxidative therapies that exploit the inherent redox vulnerabilities of cancer cells.

Immunologically “cold” tumors, characterized by low immune cells infiltration, represent a significant obstacle to the success of immune checkpoint therapy. Intestinal microbiome therapy has emerged as a potential strategy to overcome this challenge by reprogramming the immune microenvironment. However, its clinical application is constrained by unresolved safety concerns. To address these challenges, we fused Escherichia coli-secreted outer membrane vesicle (OMV) with the macrophage membrane vector (RV) to construct hybrid nanovesicle (ROMV) and encapsulated the bacterial metabolite trimethylamine N-oxide (TMAO), forming ROMV/TMAO. ROMV/TMAO mimicked the beneficial functions of intestinal probiotics by leveraging the immunomodulatory properties of OMV and TMAO, combined with the tumor-homing capabilities of RV. In human lung cancer organoids and multiple tumor models, selective tumor targeting and accumulation of ROMV/TMAO facilitated M1 polarization of tumor-associated macrophages and enhanced CD8+ T lymphocyte infiltration, ultimately inhibiting tumor growth. When combined with ROMV/TMAO, the immune checkpoint inhibitor α-PD-L1 exhibited superior antitumor efficacy than monotherapy. This study introduces a probiotic-inspired nanotherapeutic strategy for augmenting immune checkpoint therapy outcomes while addressing microbiome therapy safety challenges.

ObjectiveTo evaluate the impact of exosomes derived from rat bone marrow mesenchymal stem cells (BM-MSCs) on the malignant properties of human colorectal cancer stem cells (CRC-CSCs) and the underlying mechanism involving epithelial–mesenchymal transition (EMT).MethodsExosomes were isolated and characterized from rat BM-MSCs. Human CRC-CSCs were enriched from HCT116 cells and subsequently treated with the exosomes. Cellular functions, including proliferation, apoptosis, cell cycle progression, migration, and invasion, were assessed using cell counting kit-8 (CCK-8), colony formation, flow cytometry, and Transwell assays, respectively. In vivo tumorigenicity and lung metastasis were evaluated using a xenograft mouse model. Expression levels of EMT markers (E-cadherin, N-cadherin, and Vimentin) were analyzed by western blot, qPCR, and immunofluorescence.ResultsBM-MSCs-derived exosomes were efficiently internalized by HCT116-CSCs. In vitro, exosome treatment significantly enhanced cell proliferation, migration, invasion, and cell cycle progression, while suppressing apoptosis. In vivo, exosomes promoted tumor growth and lung metastasis. Mechanistically, exosome exposure induced EMT, as evidenced by decreased E-cadherin expression and increased expression of N-cadherin and vimentin in both in vitro and in vivo models.ConclusionExosomes derived from rat BM-MSCs enhance the malignant phenotype and suppress apoptosis in human CRC-CSCs through the activation of the EMT pathway. These findings underscore the potential role of BM-MSC-derived exosomes in tumor microenvironment (TME) regulation and highlight their relevance as a potential therapeutic target.

ABSTRACTImmune checkpoint blockade has become an effective strategy for inhibiting tumor growth, especially immune checkpoint inhibitors that target the programmed death 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) pathway, which have shown significant effects in tumor immunotherapy. In this study, we found that naturally sourced Cordyceps militaris extract can effectively downregulate the protein expression level of PD‐L1 in human colorectal cancer cell lines. Further systematic isolation, purification, and analysis of its active components revealed that cordycepin (COR) is the key active molecule mediating PD‐L1 degradation. Mechanistically, COR specifically and selectively targets the ubiquitin E3 ligase HMG‐CoA reductase degradation protein 1, thus promoting the degradation of PD‐L1 protein through the ubiquitin–proteasome pathway. This process significantly enhances the cytotoxic killing effect of effector T lymphocytes against colorectal cancer cells, ultimately achieving robust antitumor effects. Furthermore, this study also revealed that COR exhibits potential synergistic therapeutic effects when combined with anti‐CTLA4 antibodies in preclinical tumor treatment. In summary, COR, as the primary bioactive component of Cordycepsmilitaris, demonstrates considerable potential to act as a small‐molecule immune checkpoint modulator and inhibitor, thereby providing a novel therapeutic strategy for the immunotherapy of colorectal cancer.

ROS-mediated antiproliferative effects of dihydrotestosterone-derived ferrocene-steroid conjugates toward human cancer cell lines of variable androgen dependence.

Human dihydroorotate dehydrogenase (DHODH) is the rate-limiting enzyme in pyrimidine de novo synthesis and represents a promising target for cancer therapy. However, current inhibitors of DHODH have limited clinical effectiveness and adverse effects. Herein, we report NK-A 17E-233I, a novel small-molecule inhibitor of the human DHODH enzyme, identified through a prospective virtual screening methodology. Molecular docking and biochemical assays show NK-A 17E-233I functions as a pure or partial competitive inhibitor with respect to the natural substrate, dihydroorotate (DHO). It adopts a distinct binding mode from classical inhibitors that target the flavin mononucleotide (FMN) binding cavity of the hydrophobic tunnel. NK-A 17E-233I exhibits selective cytotoxicity in both human cancer cell lines and patient-derived intestinal organoids, inducing DNA damage, S-phase arrest, and cell death. Unlike Brequinar, NK-A 17E-233I preserves mitochondrial respiration via complexes I and II and maintains ATP-linked basal respiration, avoiding the impairment of the electron transport chain (ETC). Our findings imply the aptitude of NK-A 17E-233I as a novel competitive inhibitor of human DHODH, representing a significant advancement in this field since the 1990s.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s13046-025-03538-w.

Background Cervical cancer, mainly caused by Human Papillomavirus infection, is a growing public health concern in Saudi Arabia. Despite the availability of effective vaccination and screening programs in the country, awareness and acceptance remain limited, particularly among women in the Asir region. This study aimed to assess knowledge and attitudes toward Human Papillomavirus and cervical cancer prevention among women in the Asir region, Saudi Arabia. Methods A cross-sectional study was conducted from January to March 2025 among women aged 18 and older in the Asir region of Saudi Arabia. A convenience sampling method was used to recruit participants. Data were collected through an online self-administered questionnaire, and multivariable logistic regression was performed to identify factors associated with knowledge and attitudes (p < 0.05). Results Among the 523 participants, 66% demonstrated good knowledge of Human Papillomavirus and cervical cancer prevention, while 56% had positive attitudes. Awareness of Human Papillomavirus and the Human Papillomavirus vaccine was observed in 62.1% and 54% of women, respectively, while knowledge of screening tests remained limited at 32.7%. Only 21% of women reported being vaccinated against Human Papillomavirus. The main barriers discouraging women from practicing Pap tests were discomfort (65.4%) and lack of knowledge (63.7%). Factors significantly associated with lower odds of having good knowledge (Adjusted Odds Ratio, AOR) included older age (41–50 years: AOR = 0.479, 95% confidence interval (CI): 0.239–0.961; 51–60 years: AOR = 0.239, 95% CI: 0.113–0.505; >60 years: AOR = 0.127, 95% CI: 0.022–0.724), lower education (secondary school: AOR = 0.483, 95% CI: 0.305–0.764), and unmarried status (single: AOR = 0.562, 95% CI: 0.327–0.965; divorced/widowed: AOR = 0.413, 95% CI: 0.218–0.784). Negative attitudes were more prevalent among older women (41–50 years: AOR = 0.327, 95% CI: 0.170–0.629; 51–60 years: AOR = 0.272, 95% CI: 0.130–0.570; >60 years: AOR = 0.102, 95% CI: 0.012–0.876). Conclusion The study demonstrated generally good knowledge and positive attitudes toward Human Papillomavirus vaccination and cervical cancer prevention among women in the Asir region; however, awareness of screening and vaccine uptake was suboptimal. Women who were older, less educated, or unmarried had lower knowledge and more negative attitudes. Targeted educational interventions through healthcare providers, school-based programs, and social media, along with improved healthcare access, are recommended to enhance awareness, encourage regular cervical cancer screening, and reduce disease burden.

There is a Limited number of studies on THO Complex Subunit 3 (THOC3) in tumors. The purpose of this study is to conduct a comprehensive analysis of various types of tumors to determine the role of THOC3 in tumor progression and to investigate its impact on immunity. Retrieved THOC3 expression data from various cancers in the TCGA database and analyzed it using R software (version 3.6.4) and its related packages; explored the differential expression of THOC3 in tumors, its correlation with prognosis, functional enrichment, and its relationship with tumor heterogeneity. The study also aimed to uncover the correlation between THOC3 and tumor immunity. THOC3 is differentially expressed in various tumors and normal samples, and is correlated with overall survival and progression-free time. The study found that THOC3 expression is strongly associated with tumor mutational burden, microsatellite deletion, and immune response. The expression of THOC3 is significantly correlated with immune cell infiltration, and THOC3 can regulate transcription output and mRNA splicing. Therefore, we speculate that THOC3 could serve as a therapeutic target for future anticancer therapies. THOC3 can serve as a novel specific biomarker for diagnosis and prognosis in pan cancer.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-20257-6.

Ovarian cancer is the leading cause of death among gynecological malignancies worldwide. Surgery and chemotherapy are the primary treatment modalities; however, their effectiveness significantly diminishes in the advanced stages of the disease. There is emerging evidence suggesting that natural products, including phytochemicals, could be beneficial in treating ovarian cancer. In this study, we employed SKOV3 cells to investigate the anticancer activity and the specific mechanisms of corylin, a principal flavonoid isolated from the fruit of Psoralea corylifolia. Corylin inhibited SKOV3 cell proliferation and colony formation in a dose-dependent manner. It also induced apoptosis through the activation of caspases and disruption of the mitochondrial membrane potential. Moreover, corylin caused G0/G1 cell cycle arrest by modifying the levels of cyclin D1 and the phosphorylated retinoblastoma protein. Further mechanistic studies demonstrated a marked downregulation of Signal transducer and activator of transcription 3 (STAT3) phosphorylation, nuclear localization, and target gene expression in corylin-treated SKOV3 cells. These findings suggest that corylin is a promising therapeutic agent for inhibiting cancer cell proliferation by targeting STAT3 in ovarian cancer.

Reduced vascular leakage correlates with breast carcinoma T regulatory cell infiltration but not with metastatic propensity.

BackgroundApproximately 50% of colorectal cancer (CRC) patients exhibit high levels of Fusobacterium nucleatum (Fn), which is associated with chemotherapy resistance. As Fn itself cannot be directly targeted for therapy in vivo, elucidating the mechanism underlying Fn-induced chemotherapy resistance is crucial, though it remains unclear.MethodsqPCR was used to analyze the correlation between Fn abundance and clinical parameters in 80 human colon cancer samples. The effect of Fn on the sensitivity of colon cancer cells to oxaliplatin was evaluated by clone formation, EdU proliferation and apoptosis assays. RNA sequencing was performed on Fn-infected colon cancer cells to identify differentially expressed genes. Mechanistic studies explored the interaction between PVT1 and ATAD3A, and the role of TLR4/NF-κB pathway in regulating PVT1 expression.ResultsqPCR experiments showed that Fn abundance was associated with later clinical stage and shorter RFS. Clone formation, EdU proliferation assay and apoptosis assay showed that Fn could change the sensitivity of colon cancer cells to oxaliplatin. Further RNA sequencing showed that Fn infection could upregulate the expression of long noncoding RNA plasmacytoma variant translocation 1 (PVT1) in colon cancer cells. The abundance of Fn in colon cancer tissues was positively correlated with the level of PVT1, and the mechanism was that PVT1 binds to AAA domain protein 3 (ATAD3A) and prevents its ubiquitination. Fn upregulates ATAD3A expression through PVT1 and inhibits ER stress-mediated cell death. In addition, in colon cancer cells co-cultured with Fn, PVT1 expression is regulated by the TLR4/NF-κB pathway.ConclusionsThis study delineates a pathway where Fn infection promotes oxaliplatin resistancein colon cancer cells by upregulating PVT1 via the TLR4/NF-κB pathway. PVT1 subsequently stabilizes ATAD3A, suppressing cell death. PVT1 is a potential target to overcome the high abundance of Fusobacterium nucleatum leading to oxaliplatin resistance in colon cancer.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12967-025-07226-3.

Background/Objectives: The Centaurea genus is characterized by many species, a broad biological diversity, and a rich secondary metabolite content. These species exhibit various biological activities, including antioxidant, anti-inflammatory, antimicrobial, antiproliferative, and wound-healing properties. However, there are limited anticancer research studies available on the species. This study aims to investigate the potential cytotoxic effects of dichloromethane (CRD) and methanol (CRM) extracts obtained from the root of the endemic Centaurea lycaonica to clarify the mechanism of apoptosis by the intrinsic pathway on the human endometrial cancer cell line RL95-2 based on phytochemical analysis. Methods: The cytotoxicity studies were performed using a Real-Time Cell Analyzer (xCELLigence) and the MTT assay. The activities of caspase 3, caspase 9, Bax, and Bcl-2 were evaluated to investigate the molecular mechanism of apoptosis. LC-HRMS determined the phytochemical content of extracts. Results: CRD and CRM had a concentration-dependent effect in increasing caspase 3 and 9 activities and Bax/Bcl-2 ratios compared to the control with low IC50 values. Conclusions: Apoptosis induction was more pronounced with CRM, which was enriched in hesperidin; this association warrants targeted validation with purified standards.

A series of dehydroabietic acid (DHAA) derivatives containing α,β-unsaturated ketone moieties were designed, synthesized and evaluated as anticancer agents. The inhibitory activities of target compounds against SW480, HepG2, MDA-MB-231 human cancer cell lines and one normal hepatocyte cell L02 cells were estimated by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay in vitro. The results indicated that the most promising compound 2g displayed the most significant effect against MDA-MB-231 cells with an IC50 value of 8.62µM, roughly 10-fold lower than that of parent compound DHAA and fourfold lower than that of 5-Fu. Mechanistic investigations showed that 2g efficiently arrested the cell cycle at the G1 phase and induced apoptosis, accompanied by the generation of intracellular reactive oxygen species (ROS), loss of mitochondrial membrane potential, and inhibition of the NF-κB signaling pathway. These results indicated that compound 2g might be a promising lead compound for further investigation.