von Hippel-Lindau (VHL) is a tumor suppressor frequently inactivated in renal cell carcinoma (RCC), and its loss is associated with aberrant DNA methylation. Here we demonstrate that VHL-deficient RCC cells are highly vulnerable to DNA methyltransferase (DNMT) inhibitors. US Food and Drug Administration-approved DNMT inhibitors, such as decitabine and azacitidine, and investigational agents including RX-3117 and SGI-1027 selectively suppressed the growth of VHL-deficient RCC cells. Mechanistically, VHL loss leads to HIF-2α-dependent transcriptional upregulation of DNMT1, resulting in widespread CpG hypermethylation. Transcriptomic profiling and an RNA interference-based rescue screen identified KCNK3, a putative tumor suppressor, as a key mediator of DNMT inhibitor-induced synthetic lethality in VHL-deficient RCC. The KCNK3 promoter is hypermethylated and transcriptionally repressed in VHL-deficient RCC, where treatment with DNMT inhibitors reverses this methylation, restoring KCNK3 expression and resulting in cell growth inhibition. Silencing KCNK3 significantly attenuated the antitumor effects of DNMT inhibitors both in vitro and in vivo. Further mechanistic analysis showed that KCNK3 reactivation triggers TNF-α, MAPK and apoptotic signaling pathways, contributing to the observed synthetic lethality. Collectively, these findings establish DNMT inhibition as a synthetic lethal strategy in VHL-deficient RCC and highlight a potential therapeutic vulnerability for personalized treatment approaches.

Endothelin-1 (ET-1) is a critical mediator of airway remodeling and subepithelial fibrosis in patients with asthma. However, the roles of casein kinase 2 (CK2), p300, and STAT3 signaling pathways in ET-1-induced connective tissue growth factor (CTGF) expression remain poorly understood. In WI-38 cells (human lung fibroblasts), pharmacological inhibitors of CK2 (apigenin and 4, 5, 6, 7-tetrabromobenzotriazole (TBB)) markedly attenuated ET-1-induced CTGF expression, and ET-1 promoted nuclear translocation of CK2. Transfection with CK2α' siRNA, but not CK2α siRNA, inhibited ET-1-induced CTGF expression, and ET-1 induced tyrosine phosphorylation of CK2α'. ET-1-induced CTGF expression was attenuated by a STAT3 dominant-negative mutant, STAT3 siRNA, or p300 inhibitor (C646). In addition, CK2α' silencing suppressed ET-1-induced phosphorylations of p300 and STAT3. ET-1-mediated STAT3 acetylation and STAT3 transcriptional activity were inhibited by transfection with p300 or CK2α' siRNA. ET-1 also induced assembly of a CK2α'/p300/STAT3/c-Jun/HDAC7 complex and its recruitment to the CTGF promoter. However, CK2α was dispensable for these CK2α'-mediated downstream signaling events. Furthermore, CK2α' knockdown attenuated ET-1-induced fibronectin, collagen I, and α-smooth muscle actin expression. Together, these findings identify CK2α' as a key regulator of ET-1-driven transcriptional complex formation that promotes profibrotic protein expressions in human lung fibroblasts.

Staphylococcus aureus forms biofilms in the context many infections, including endocarditis, lung infection, and the colonization of implants. How antimicrobials specifically affect S. aureus biofilms as opposed to planktonic S. aureus is an important consideration in the development of treatments of these infections. It is well known that bacteria in biofilms are more resistant to antimicrobials, and the degree and nature of the responses is crucial to understanding the basis of this resistance. While certain antimicrobials such as antibiotics have specific mechanisms that induce pathways related to those mechanisms, and others such as hypochlorite are highly toxic, a wide variety of compounds exhibit intermediate effects that affect multiple systems. Responses to these substances are important to understand if new therapeutics are to be designed. Here, we investigated antibacterial and antibiofilm effects of cinnamaldehyde (CmAl), an antibacterial agent commonly used in foods. CmAl affects multiple bacterial systems, providing a model for the characterization of these intermediate responses. We measured CmAl activity on established biofilm and planktonic bacteria using recombinant bioluminescent S. aureus and performed RNA-seq on CmAl-treated biofilms and planktonic bacteria. RNA-seq results revealed response pathways that differ between these states, including phosphate uptake. The results of this study demonstrate how CmAl differentially affects S. aureus biofilms compared to planktonic forms.

Organic anion transporting polypeptide (OATP) 1B3 plays a clinically significant role in hepatic drug disposition. Lysine acetylation, a key post-translational modification, has not been investigated for OATP1B3. This study determined the lysine acetylation status of OATP1B3 by proteomics and assessed the impact of inhibition of lysine deacetylase (KDAC) 6, a major cytosolic KDAC, on OATP1B3 acetylation and transport function. Proteomics revealed 7 acetylation sites, including 5 with additional ubiquitin-like modifications, and 4 phosphorylation sites (T10, S293, S295, S683). In human embryonic kidney 293 (HEK293)-Myc-FLAG-OATP1B3 cells, preincubation with the selective KDAC6 inhibitor tubacin (TBC) (5 μM, 24 hours), markedly reduced OATP1B3-mediated transport of [3H]cholecystokinin-8 (CCK-8), a specific substrate, and [3H]estradiol-17β-D-glucuronide to 0.15 ± 0.03-fold and 0.19 ± 0.01-fold of the control, respectively, without affecting OATP1B3 mRNA, protein levels, or membrane localization determined by real-time reverse transcription polymerase chain reaction, immunoblotting, and confocal microscopy. TBC treatment increased K664 acetylation to 2.12 ± 1.03-fold of the control (P < .05). Consistently, the acetylation-mimetic K664Q variant exhibited reduced transport compared with the acetylation-null K664R variant (P < .05). Treatment with a second KDAC6 selective inhibitor, WT-161 (3 μM, 5 hours), similarly reduced OATP1B3-mediated [3H]CCK-8 transport. In cultured primary human hepatocytes, TBC treatment for 4, 8, and 24 hours decreased [3H]CCK-8 transport to 0.34 ± 0.02-fold, 0.27 ± 0.03-fold, and 0.37 ± 0.03-fold of the control, respectively (all P < .05). The study reveals a novel post-translational modification of OATP1B3 by lysine acetylation and demonstrates impaired transporter function following KDAC6 inhibition, likely involving increased acetylation at K664, thereby providing new insight into OATP1B3-mediated drug-drug interactions driven by KDAC6 activity. SIGNIFICANCE STATEMENT: This study identifies lysine acetylation as a novel post-translational modification of organic anion transporting polypeptide (OATP)1B3 and demonstrates that altered lysine acetylation following inhibition of lysine deacetylase 6 reduces OATP1B3 transport function. These findings provide a mechanistic basis for altered hepatic drug disposition and highlight a new pathway through which drug-drug interactions involving OATP1B3 may occur.

Gallium nitrate, a non-redox analog of iron (III), suppresses bacterial biofilms and virulence within the framework of bacterial regulation. This study investigates the molecular mechanisms and regulatory pathways through which gallium nitrate modulates bacterial activity and function.

Osteomyelitis is a bacterial infection of the bone that affects millions globally. Due to problems in drug delivery, bacterial resistance through biofilm formation, adverse effects of the medications in use, etc, the scientists are searching for novel antimicrobial agents. As drug repurposing is an excellent method to develop new antimicrobials, this study evaluates the antibacterial and antibiofilm effects of the antidepressant paroxetine, combined with hydroxyapatite (HA), against drug-resistant, biofilm-forming Staphylococcus aureus. The antibacterial activity of paroxetine was assessed using the agar diffusion assay, and the minimum inhibitory concentration (MIC) was determined by the microdilution method. The antibiofilm potential of paroxetine was quantified through the crystal violet assay and further examined using scanning electron microscopy and confocal laser scanning microscopy. The bacterial load on drug-loaded hydroxyapatite was determined using the viable colony count method. The expression of bacterial adhesion genes following paroxetine treatment was analyzed using real-time polymerase chain reaction. Molecular docking studies were performed to evaluate the binding affinity of paroxetine to bacterial adhesion proteins and penicillin-binding proteins. The study demonstrated promising antibacterial properties of the drug and the drug-HA combination against S aureus with a MIC of 18.75 µg/mL. Paroxetine prevented the biofilms formation by S aureus, and could eradicate mature biofilms, with 83%, 86%, and 89% efficacy after 1X MIC, and 2X treatment. The antibiofilm effect was further confirmed by in silico, in vitro methods, wherein a strong affinity was noted for biofilm adhesion protein and paroxetine. Paroxetine treatment revealed downregulation of biofilm-adhering genes, like icaA, clfA, cna, fnbpA, and fib, using RT-PCR. When combined with HA, paroxetine displayed synergistic activity, and this was visualized using confocal laser scanning microscopy, which showed 81% and 19% dead/live cells after treatment, respectively. Furthermore, the scanning electron microscopy analysis displayed the impact of the drug paroxetine on S aureus cell morphology, which showed remarkable damage to the bacterial cells. In silico docking revealed that paroxetine's mode of action was mediated through binding with proteins and penicillin-binding protein, thereby inducing cell death. These results suggest that the paroxetine-HA combination may serve as a promising adjunctive strategy for treating biofilm-associated infections caused by S aureus.

This study aimed to investigate the molecular mechanisms underlying BPA(Bisphenol A)-induced cervical cancer, to identify core targets and signaling pathways, and to provide a theoretical basis for disease prevention and therapeutic intervention. The chemical structure of BPA was obtained from PubChem(Public Chemical Database), and its toxicity profile was evaluated using ProTox-3.0. Potential BPA-associated targets were predicted using multiple databases and subsequently standardized. Differentially expressed genes (DEGs) in cervical cancer were identified from Gene Expression Omnibus datasets using the R programming language and integrated with Weighted Gene Co-expression Network Analysis (WGCNA) to determine key module genes. The cervical cancer-related target set was then established. Common targets between BPA and cervical cancer were identified using Venn diagram analysis, and a protein-protein interaction (PPI) network was constructed to screen for core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to explore biological functions and pathways. Target gene expression was validated across multiple datasets, and molecular docking analysis was conducted using Cavity-Based Dock 2 (CB-Dock2). BPA exhibits endocrine toxicity and matrix metalloproteinase-mediated tissue damage, with 3 core targets identified across databases. In cervical cancer, 803 up-regulated and 1092 down-regulated DEGs were screened (|log2FC| ≥1, adjusted P <.05). WGCNA identified the turquoise module (normal group R = 0.98, P = 5 × 10-12; cancer group r = -0.98, P = 5 × 10-12), overlapping with 1110 DEGs. Nineteen common targets of BPA and cervical cancer were enriched in gene expression negative regulation and cancer pathways (hypergeometric test, false discovery rate (FDR) <0.05). PPI analysis confirmed Estrogen Receptor 1 (ESR1) and (Poly [ADP-ribose] Polymerase 1 (PARP1) as core targets: ESR1 was down-regulated (GSE122697: log2FC = -2.8, P <.0001; The Cancer Genome Atlas (TCGA): log2FC = -2.6, P <.0001), PARP1 up-regulated (GSE122697: log2FC = 3.1, P <.0001; TCGA: log2FC = 2.9, P = .0012). Both showed progressive expression changes with lesion advancement (GSE63514: ESR1 log2FC = -4.2, PARP1 log2FC = 4.5, P <.0001). Molecular docking revealed stable binding of BPA to ESR1 (-8.3 kcal/mol) and PARP1 (-8.5 kcal/mol, root-mean-square deviation [RMSD] <2.0 A). BPA may promote cervical carcinogenesis by interacting with ESR1 and PARP1 to regulate key cancer-related pathways. These targets may serve as potential biomarkers and therapeutic intervention points. Further experimental validation is required to confirm these findings.

Plastic stabilizers (PSs) are chemical additives that are widely used to inhibit the degradation of plastics. However, their safety concerns and potential carcinogenic risks remain unclear. This study employed network toxicology strategies to elucidate the potential toxic effects and underlying molecular mechanisms of representative PSs, including 2,6-di-tert-butylphenol (2,6-DTB), tert-butylhydroquinone (TBHQ), and 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV-328) in breast cancer (BC). Herein, we identified 69 potential genes related to PSs exposure and BC, and optimized five core targets: GSK3B, MAPK14, PARP1, PIM1, and TRDMT1, through subsequent LASSO and SVM algorithms. Based on these core genes, we constructed risk score and nomogram models, both of which revealed that high expression of these five core genes predicts poor prognosis in BC patients. Additionally, molecular docking and dynamic simulations indicated high-affinity interactions between PSs and these core targets (binding energies < -5 kcal/mol). Further correlation analysis with prediction analysis of microarray 50 (PAM50) revealed increased expression of all core genes in the basal-like subtype, especially PIM1 and TRDMT1, which also exhibited the highest risk scores. In vitro, PSs transcriptionally upregulated MAPK14, PIM1, and TRDMT1, with STAT3 mediating their transcription. Importantly, cell counting kit-8 and wound healing assays demonstrated that PSs promote BC cell proliferation and migration. Our research re-evaluates the carcinogenic risks of plastic stabilizers and suggests that PSs may enhance breast cancer progression via targets such as MAPK14, PIM1, and TRDMT1. This study introduces a new approach for evaluating the safety of plastic additives and offers novel insights into the toxicological effects of PSs.

Hyperuricemic nephropathy (HN) is a progressive kidney disease resulting from impaired urate metabolism, with limited effective therapies using natural sources. Sea cucumber peptides (SCPs) have shown metabolic regulatory potential in chronic diseases, but their efficacy in HN and underlying mechanisms remain unclear. This study investigated SCPs' effects using hyperuricemic mouse models and HK-2 cells. Interestingly, SCPs did not inhibit xanthine oxidase activity, yet significantly reduced serum uric acid (UA) levels, improved renal function, and attenuated pathological damage in mice. Mechanistically, SCPs reversed HN-induced metabolic reprogramming by downregulating key glycolytic enzymes (HK2, PFKFB3, and LDHA), reducing lactate accumulation, and enhancing ATP production. Multi-omics analyses revealed that SCPs optimized glycolysis-TCA cycle flux. Crucially, SCPs restored lactylation homeostasis via the SIRT1/p300 axis, suppressing global protein and histone lactylation. Concurrently, SCPs inhibited the HIF-1α/NF-κB/STAT3 pathway, decoupling metabolic-inflammatory signaling. These findings demonstrate that SCPs alleviate HN through multi-targeted regulation of urate metabolism, metabolic reprogramming, and lactylation, offering a novel strategy for functional food development.

Abnormal activation and pyroptosis of microglia caused by cerebral ischemia‑reperfusion injury (CIRI) are key mechanisms underlying neuronal damage. The NF‑κB/NLRP3 pathway is a core mediator of microglial pyroptosis and neuroinflammatory cascades in CIRI. Milk fat globule‑EGF factor 8 (MFG‑E8) is a critical anti‑inflammatory and neuroprotective factor. Propofol (PPF) exhibits antioxidant activity and ameliorates neuronal injury, but its effects on CIRI and underlying mechanisms remain unclear. The present study aimed to investigate whether PPF alleviates neuronal injury by modulating NF‑κB/NLRP3 pathway via regulating MFG‑E8 expression. An oxygen‑glucose deprivation/reoxygenation (OGD/R) model was established using mouse microglial BV‑2 and hippocampal neuronal HT22 cells and cell survival was assessed via Cell Counting Kit‑8 assay. Polarity in BV‑2 cells was evaluated using flow cytometry, while cell death was assessed by Calcein AM/PI and TUNEL staining. A transient middle cerebral artery occlusion (tMCAO) mouse model was established and neurological deficit scores were assessed. The impacts of PPF on cortical damage, neuroinflammation, apoptosis and pyroptosis in tMCAO mice were observed by histopathological staining. Inflammatory factor levels were assessed using ELISA kits. Western blotting was performed to assess MFG‑E8, pyroptosis and NF‑κB/NLRP3 pathway‑related proteins. OGD/R decreased viability, increased apoptosis and pyroptosis rates in BV‑2 and HT22 cells and promoted M1 polarization in BV‑2 cells; PPF treatment reversed these effects. MFG‑E8 was downregulated in OGD/R‑treated BV2 cells, while PPF upregulated MFG‑E8 expression. Additionally, PPF decreased cerebral infarction volume in tMCAO mice, improved neurological deficit score, mitigated pathological brain tissue damage and decreased the number of degenerating neurons. PPF also inhibited pro‑inflammatory microglia activation and decreased pro‑inflammatory factor levels. Mechanistically, PPF suppressed NF‑κB pathway activation and downregulated NLRP3 by upregulating MFG‑E8; silencing MFG‑E8 reduced the protective effects of PPF in tMCAO mice and OGD/R cell models. PPF improved neuronal injury in CIRI by upregulating MFG‑E8 to inhibit pyroptosis induced by the NF‑κB/NLRP3 pathway.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies worldwide. Cisplatin, a widely used chemotherapeutic agent, exerts its anticancer effect by inducing DNA damage, and inhibiting transcription and replication. However, its repeated administration can lead to severe side effects and the development of drug resistance, thereby limiting its clinical efficacy. Thus, novel combination strategies are urgently needed to enhance the anticancer effects of cisplatin. The present study aimed to investigate the potential of Platycodin D (PD), a natural saponin extracted from Platycodon grandiflorus, to enhance cisplatin sensitivity in HNSCC cells. The results demonstrated that combination treatment with PD and cisplatin synergistically reduced cell viability and markedly suppressed colony formation compared with either agent alone. Furthermore, the combination treatment markedly increased intracellular reactive oxygen species (ROS) levels, and markedly downregulated the expression levels of antioxidant genes, including heme oxygenase‑1, NAD(P)H quinone dehydrogenase 1, superoxide dismutase 1 and sulfiredoxin 1. Additionally, the combination treatment excessively activated autophagy, whereas PD inhibited autophagic flux, as determined by LC3A/B and p62 accumulation following Bafilomycin A1 treatment, ultimately promoting apoptosis. These findings suggested that PD may serve as a potential cisplatin sensitizer by enhancing ROS accumulation and disrupting autophagy, thereby presenting a promising combination therapeutic strategy for the treatment of HNSCC.

Pancreatic cancer remains one of the deadliest tumor diseases with an urgent need for new therapy options. At the same time, the use of high‑dose vitamin C in cancer treatment has been investigated for decades. Despite promising in vitro and in vivo data and initial clinical studies, there is a need for optimization with regard to an ideal treatment regimen and suitable patient population for the use of high‑dose vitamin C. The aim of the present study was to evaluate for the first time the combination of high‑dose vitamin C with the administration of iron in three human pancreatic cancer cell lines and to determine the exact cell death mechanism. While the investigated cell lines showed a high susceptibility to ascorbate treatment, the combination treatment with FeCl3 generally led to a reduction in the ascorbate effect and in the formation of reactive oxygen species. The ascorbate‑induced cell death showed no signs of apoptosis but clear ferroptotic properties. Furthermore, treatment of the tumor cells with FeCl3 was accompanied by reduced expression of TfR1, preventing an increase in the intracellular labile iron pool. The present study provided valuable information on the mechanism of action of high‑dose vitamin C in pancreatic cancer, whereby a combination treatment with ferric iron in the context of tumor therapy is not recommended based on these data.

Accumulating evidence indicates that environmental exposures, particularly to nitrites, play a critical role in the initiation and progression of gastric cancer (GC). During carcinogenesis, exosomes act as key mediators of intercellular communication. Exosomes derived from N‑methyl-N'‑nitro‑N‑nitrosoguanidine (MNNG)‑induced malignantly transformed GES‑1 cells (TGES‑1), as well as serum exosomes from gastric cancer patients with a history of high nitrite exposure, were found to influence normal cells and promote GC initiation. The present study established a malignant transformation model and applied bioinformatics analyses to screen and validate candidate circRNAs. A series of functional and mechanistic experiments were performed to elucidate the regulatory role of exosomes in GC progression. Circ0000549 was markedly upregulated in MNNG‑exposed GES‑1 cells, their derived exosomes and serum exosomes from patients with GC. Further investigations revealed that circ0000549 overexpression enhanced GES‑1 cell malignant features, while also modulating epithelial‑mesenchymal transition and stemness‑related properties. Nude mouse experiments demonstrated that circ0000549, carried by malignantly transformed exosomes, plays a crucial role in MNNG‑induced gastric carcinogenesis. Mechanistically, miR‑15b‑5p was identified as a potential target of circ0000549. Circ0000549 functioned as a sponge for miR‑15b‑5p, leading to increased KIF1B expression and subsequent activation of the PI3K/AKT signaling pathway. Collectively, these findings reveal that exosomal circ0000549 promotes malignant transformation of GES‑1 cells through the miR‑15b‑5p/KIF1B/PI3K/AKT axis. Exosomal circ0000549 may serve as a promising biomarker for GC diagnosis and prognosis, highlighting its potential as a target for future therapeutic investigation.

Chemoresistance is a major cause of cancer therapy failure. Increasing evidence points to the importance of histone lysine demethylase function, whose dysregulation has been described in several types of cancer. KDM5, a family of histone lysine demethylases, may carry out a key role in the downregulation of tumor‑suppressors or upregulation of oncogenes and in the development of drug tolerance. The present study examined the expression of KDM5D in cell lines derived from high‑risk neuroblastoma. The present study found that KDM5D expression was lost in all cisplatin‑chemoresistant neuroblastoma cell lines compared with sensitive parental cells. In addition, the cisplatin‑chemoresistant neuroblastoma cell line had increased expression of the ubiquitin ligase cullinaA 4A (CUL4A) compared with the sensitive parental cells. CUL4A carries out a role in cellular processes and its aberrant regulation has been observed in a number of types of cancer. The present study shows that silencing of KDM5D causes a more aggressive phenotype of neuroblastoma by promoting cell proliferation and migration, evading cell death, promoting S phase of the cell cycle and desensitizing sensitive cells to cisplatin via the gene CUL4A. In addition, ectopic expression of KMD5D in a cisplatin‑resistant cell line reversed these phenomena. The results suggest that KDM5D and/or CUL4A may be a biomarkers of chemoresistance to cisplatin and a potential therapeutic target in neuroblastoma.

Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. Intensifying chemotherapy has failed to improve patient survival for metastatic or relapsed RMS and RMS survivors often suffer from significant long‑term toxicities. More efficient and less toxic new therapies are critically needed. RMS expresses high levels of anti‑apoptotic protein Bcl‑2 and an oncogenic transcription factor Forkhead box protein M1 (FOXM1), which is also known to inhibit tumor cell apoptosis. The present study used a combination therapy of a recently developed non‑toxic FOXM1 inhibitor, RCM‑1 and the FDA‑approved Bcl2 inhibitor, venetoclax, which is not effective as a monotherapy in solid tumors. Compared with venetoclax alone, the combination therapy efficiently inhibited RMS growth in the animal model by decreasing tumor cell proliferation and inducing tumor cell apoptosis. RNA‑sequencing analysis demonstrated that the combination therapy uniquely decreased expression of ATPase Plasma Membrane Ca2+ Transporting 4 (ATP2B4), a plasma membrane calcium channel that is highly expressed in RMS compared with normal muscle cells. RCM‑1, but not venetoclax treatment, inhibited ATP2B4 and enhanced the sensitivity of RMS cells to apoptosis. Knockdown of ATP2B4 decreased RMS tumor cell proliferation, migration and colony formation in vitro. Furthermore, knockdown of ATP2B4 increased tumor cell apoptosis, while overexpression of ATP2B4 decreased tumor cell apoptosis in vitro. In the animal model of RMS, depletion of ATP2B4 decreased tumor growth. In summary, combining RCM‑1 with venetoclax sensitized RMS cells to apoptosis by decreasing ATP2B4. This made ATP2B4 a promising therapeutic target for RMS and provides a rationale for exploring this combination in early‑stage clinical trials.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a dismal 5‑year survival rate of ~9%, primarily due to late diagnosis, aggressive metastasis and profound resistance to conventional therapies. Epithelial‑mesenchymal transition (EMT) has been identified as a pivotal driver of these malignant phenotypes, facilitating early invasion, dissemination and treatment failure. The present review systematically elaborated on the multidimensional mechanisms underlying EMT in PDAC, emphasizing its operation as a spectrum of hybrid epithelial/mesenchymal states rather than a binary switch. Key molecular mechanisms include the activation of core transcription factors (such as Snail, ZEB, Twist), intricate crosstalk within the tumor microenvironment (such as transforming growth factor-β and hepatocyte growth factor signaling from stromal cells) and dynamic epigenetic reprogramming. Furthermore, EMT critically contributes to the acquisition of cancer stem cell properties and enhances the survival and colonization of circulating tumor cells. The present review also outlined emerging translational strategies targeting EMT‑related pathways, highlighting agents such as STNM01 that have entered early-phase clinical trials. By synthesizing unprecedented insights into EMT's plastic spectrum states and subtype‑specific regulatory networks, this work establishes a paradigm‑shifting framework for advancing EMT‑targeted therapies; offering transformative potential to overcome PDAC's historical therapeutic barriers and substantially improve patient survival outcomes. By synthesizing current insights from molecular pathways to therapeutic applications, the present review confirmed EMT as a promising therapeutic target and provides a strategic framework for advancing PDAC treatment, with the ultimate goal of improving clinical outcomes.

Diffuse large B‑cell lymphoma (DLBCL), the most prevalent subtype of lymphoma, is characterized by rapid growth and a poor prognosis, with the R‑CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) being the standard first‑line therapy. However, 30‑40% of patients experience early relapse or refractoriness to treatment, highlighting the need to understand the mechanisms of chemoresistance. The present review synthesizes the current knowledge on the molecular mechanisms underlying chemoresistance in DLBCL, including genetic mutations, epigenetic modifications, aberrant activation of signaling pathways, alterations in drug metabolism and efflux, and upregulation of anti‑apoptotic proteins. In addition, the role of the tumor microenvironment in mediating therapeutic resistance is discussed and biomarkers associated with chemoresistance are explored. Furthermore, novel therapeutic strategies targeting chemoresistance, such as immunotherapy, metabolic modulators and epigenetic therapies, are examined. Understanding these mechanisms is crucial for developing effective treatment strategies to overcome resistance and improve patient outcomes in DLBCL.

Sex hormone-binding globulin (SHBG) is a sex hormone carrier. We aimed to characterize the role of pregnane X receptor (PXR), a major regulator of drug metabolism, in SHBG regulation. Serum SHBG was measured in four clinical trials (n = 61) and expression in in vitro experiments in human 3D hepatocyte spheroids and HepG2 cells. We also analysed previously published chromatin immunoprecipitation sequencing data from cryopreserved human hepatocytes. One-week dosing of PXR ligand rifampicin increased SHBG in all but one healthy volunteer (geometric mean induction 2.0-fold; SHBG concentration 70.5 ± 34.1 nmol/L with rifampicin and 36.1 ± 19.0 nmol/L with control; p < 0.0001; 95% confidence interval of the mean of differences between arms 31.9-42.0). In men, serum total testosterone increased and free androgen index decreased. In 3D human hepatocyte spheroids, rifampicin caused a clear induction of SHBG mRNA, while SPA70, a PXR antagonist, decreased both basal and rifampicin-induced SHBG mRNA expression. Analysis of ChIP-sequencing data identified a rifampicin-induced PXR binding site within the SHBG gene. These results show that PXR is a novel regulator of serum SHBG in humans. This mechanism may mediate effects of PXR-activating drugs and other chemicals on sex hormone balance and have implications for metabolic health.

Age-specific biological differences in breast cancer (BC) shape the disease course, therapeutic sensitivity, and prognosis. The microRNAs hsa-miR-26b-5p and hsa-miR-186-5p are considered promising biomarkers of tumor aggressiveness and treatment response, yet their age-dependent expression features remain insufficiently characterized.

Temozolomide (TMZ) based chemotherapy remains the standard frontline treatment for advanced pancreatic neuroendocrine tumors (PNETs). However, the therapeutic efficacy is frequently compromised by primary or acquired resistance, and the underlying mechanisms beyond MGMT expression remain poorly understood. In this study, we identify acetyl coenzyme A synthetase 2 (ACSS2) as a critical driver of TMZ resistance in PNETs through a metabolic epigenetic signaling axis. Integrated single-cell RNA sequencing and clinical cohort analyses reveal that ACSS2 is significantly upregulated in PNETs and positively correlates with a chemoresistant transcriptomic profile. Mechanistically, ACSS2 mediated acetate metabolism facilitates histone hyperacetylation, which directly promotes the transcription of BCL6, a potent transcriptional repressor. BCL6 in turn binds to the promoter of the master tumor suppressor TP53 and silences its expression, thereby bypassing TMZ induced G2/M arrest and suppressing apoptosis. Pharmacological inhibition or genetic ablation of the ACSS2/BCL6 axis restores P53 mediated DNA damage response and re-sensitizes PNET cells to TMZ. Notably, combined treatment with an ACSS2 inhibitor and anti-PD1/L1 immunotherapy demonstrates superior synergistic efficacy in patient derived organoids and immunocompetent Rip1-Tag2 mice. This study delineates a non-redundant metabolic epigenetic barrier to chemotherapy and suggests that targeting the ACSS2/BCL6/P53 axis represents a promising strategy to overcome chemoresistance in PNET patients.