J Chem Inf Model. 2025 May 16. doi: 10.1021/acs.jcim.5c00435. Online ahead of print.

ABSTRACT

Drug repositioning, which identifies novel therapeutic applications for existing drugs, offers a cost-effective alternative to traditional drug development. However, effectively capturing the complex relationships between drugs and diseases remains challenging. We present HGCL-DR, a novel heterogeneous graph contrastive learning framework for drug repositioning that effectively integrates global and local feature representations through three key components. First, we introduce an improved heterogeneous graph contrastive learning approach to model drug-disease relationships. Second, for local feature extraction, we employ a bidirectional graph convolutional network with a subgraph generation strategy in the bipartite drug-disease association graph, while utilizing a graph diffusion process to capture long-range dependencies in drug-drug and disease-disease relation graphs. Third, for global feature extraction, we leverage contrastive learning in the heterogeneous graph to enhance embedding consistency across different feature spaces. Extensive experiments on four benchmark data sets using 10-fold cross-validation demonstrate that HGCL-DR consistently outperforms state-of-the-art baselines in both AUPR, AUROC, and F1-score metrics. Ablation studies confirm the significance of each proposed component, while case studies on Alzheimer's disease and breast neoplasms validate HGCL-DR's practical utility in identifying novel drug candidates. These results establish HGCL-DR as an effective approach for computational drug repositioning.

PMID:40377926 | DOI:10.1021/acs.jcim.5c00435

Tissue Barriers. 2025 May 16:2503523. doi: 10.1080/21688370.2025.2503523. Online ahead of print.

ABSTRACT

Vascular endothelial barrier disruption is a critical determinant of morbidity and mortality in sepsis. Whole blood represents a key source of paracrine signaling molecules inducing vascular endothelial barrier disruption in sepsis. This study analyzes whole-genome transcriptome data from sepsis patients' whole blood available in the NCBI GEO database to identify paracrine mediators of vascular endothelial barrier dysfunction, uncovering novel insights that may guide drug repositioning strategies. This study identifies the regulated expression of paracrine signaling molecules TFPI, MMP9, PROS1, JAG1, S1PR1, and S1PR5 which either disrupt or protect vascular endothelial barrier function in sepsis and could serve as potential targets for repositioning existing drugs. Specifically, TFPI (barrier protective), MMP9 (barrier destructive), PROS1 (barrier protective), and JAG1 (barrier destructive) are upregulated, while S1PR1 (barrier protective) and S1PR5 (barrier protective) are downregulated. Our observations highlight the importance of considering both protective and disruptive mediators in the development of therapeutic strategies to restore endothelial barrier integrity in septic patients. Identifying TFPI, MMP9, PROS1, JAG1, S1PR1, and S1PR5 as druggable paracrine regulators of vascular endothelial barrier function in sepsis could pave the way for precision medicine approaches, enabling personalized treatments that target specific mediators of endothelial barrier disruption to improve patient outcomes in sepsis.

PMID:40376886 | DOI:10.1080/21688370.2025.2503523

Trends Cancer. 2025 May 15:S2405-8033(25)00106-2. doi: 10.1016/j.trecan.2025.04.010. Online ahead of print.

ABSTRACT

The acknowledged relationship between metabolism and cancer retains important potential as a novel target in therapy. Reallocating glucose-lowering drugs (GLDs) in cancer treatment offers valuable perspectives for the ability of these molecules to regulate metabolism at cellular and systemic level. This comprehensive review addresses the therapeutic potential of the main antidiabetic classes of glucose-lowering drugs with emerging anticancer effects, such as metformin, rosiglitazone, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium/glucose cotransporter-2 inhibitors. The multifaceted actions of these drugs are explored, from in vitro evidence to clinical evidence as monotherapy or as a sparing agent with chemotherapy and immunotherapy. For each molecule, unconventional mechanisms, benefits, and limitations are dissected and possible concerns addressed, supporting evidence for the potential use of the drug in cancer.

PMID:40374399 | DOI:10.1016/j.trecan.2025.04.010

J Mol Graph Model. 2025 May 10;139:109076. doi: 10.1016/j.jmgm.2025.109076. Online ahead of print.

ABSTRACT

The hallmark of Alzheimer's disease (AD), a progressive neurodegenerative condition, is the buildup of amyloid-beta (Aβ) plaque, which is mainly caused by β-secretase 1 (BACE-1) activity. BACE-1 inhibition is a potentially effective treatment strategy to lower the progression of AD. In order to find possible BACE-1 inhibitors using a drug repurposing technique, this study uses an integrated computational approach that includes pharmacophore modelling, virtual screening, molecular docking, MM-GBSA, molecular dynamics (MD) simulations, in-silico ADMET profiling, and PBPK modelling. A pharmacophore model, was created with known BACE-1 inhibitors to enable virtual screening of both novel and FDA-approved chemical libraries. Top candidates with good free energy scores and strong binding affinities were found using molecular docking and MM-GBSA calculations. The stability of shortlisted Hits inside the BACE-1 active site was further validated using MD simulations, which showed that some of the important interactions were maintained across a period of 50ns. ADMET and PBPK studies predicted favorable pharmacokinetic and safety profiles for the shortlisted hits, particularly for B2 and B9. These findings identify potential candidates for future experimental validation, offering an inexpensive approach for identification of compounds as potential BACE-1 inhibitors.

PMID:40373679 | DOI:10.1016/j.jmgm.2025.109076

Protein Sci. 2025 Jun;34(6):e70156. doi: 10.1002/pro.70156.

ABSTRACT

Since the emergence of SARS-CoV-2 at the end of 2019, the virus has caused significant global health and economic disruptions. Despite the rapid development of antiviral vaccines and some approved treatments such as remdesivir and paxlovid, effective antiviral pharmacological treatments for COVID-19 patients remain limited. This study explores Nsp15, a 3'-uridylate-specific RNA endonuclease, which has a critical role in immune system evasion and hence in escaping the innate immune sensors. We conducted a comprehensive drug repurposing screen and identified 44 compounds that showed more than 55% inhibition of Nsp15 activity in a real-time fluorescence assay. A validation pipeline was employed to exclude unspecific interactions, and dose-response assays confirmed 29 compounds with an IC50 below 10 μM. Structural studies, including molecular docking and x-ray crystallography, revealed key interactions of identified inhibitors, such as TAS-103 and YM-155, with the Nsp15 active site and other critical regions. Our findings show that the identified compounds, particularly those retaining potency under different assay conditions, could serve as promising hits for developing Nsp15 inhibitors. Additionally, the study emphasizes the potential of combination therapies targeting multiple viral processes to enhance treatment efficacy and reduce the risk of drug resistance. This research contributes to the ongoing efforts to develop effective antiviral therapies for SARS-CoV-2 and possibly other coronaviruses.

PMID:40371758 | DOI:10.1002/pro.70156

Brief Bioinform. 2025 May 1;26(3):bbaf215. doi: 10.1093/bib/bbaf215.

ABSTRACT

Monkeypox (Mpox) is a major global human health threat after COVID-19. Its treatment becomes complicated with type-2 diabetes (T2D). It may happen due to the influence of both disease-causing common host key genes (cHKGs). Therefore, it is necessary to explore both disease-causing cHKGs to reveal their shared pathogenetic mechanisms and candidate drugs as their common treatments without adverse side effect. This study aimed to address these issues. At first, 3 transcriptomics datasets for each of Mpox and 6 T2D datasets were analyzed and found 52 common host differentially expressed genes (cHDEGs) that can separate both T2D and Mpox patients from the control samples. Then top-ranked six cHDEGs (HSP90AA1, B2M, IGF1R, ALD1HA1, ASS1, and HADHA) were detected as the T2D-causing cHKGs that are associated with the complexity of Mpox through the protein-protein interaction network analysis. Then common pathogenetic processes between T2D and Mpox were disclosed by cHKG-set enrichment analysis with biological processes, molecular functions, cellular components and Kyoto Encyclopedia of Genes and Genomes pathways, and regulatory network analysis with transcription factors and microRNAs. Finally, cHKG-guided top-ranked three drug molecules (tecovirimat, vindoline, and brincidofovir) were recommended as the repurposable common therapeutic agents for both Mpox and T2D by molecular docking. The absorption, distribution, metabolism, excretion, and toxicity and drug-likeness analysis of these drug molecules indicated their good pharmacokinetics properties. The 100-ns molecular dynamics simulation results (root mean square deviation, root mean square fluctuation, and molecular mechanics generalized born surface area) with the top-ranked three complexes ASS1-tecovirimat, ALDH1A1-vindoline, and B2M-brincidofovir exhibited good pharmacodynamics properties. Therefore, the results provided in this article might be important resources for diagnosis and therapies of Mpox patients who are also suffering from T2D.

PMID:40370100 | DOI:10.1093/bib/bbaf215

Indian J Microbiol. 2025 Mar;65(1):347-358. doi: 10.1007/s12088-024-01280-z. Epub 2024 Apr 18.

ABSTRACT

Antibiotic resistance in urinary tract infections (UTIs) is a growing concern due to extensive antibiotic use. The study explores a drug repurposing approach to find non-antibiotic drugs with antibacterial activity. In the present study, 8 strains of Pseudomonas spp. were used that were clinically isolated from UTI-infected patients. Amlodipine, a cardiovascular drug used in this study, has shown potential antimicrobial effect in reducing the various virulence factors, including swimming and twitching motility, biofilm, rhamnolipid, pyocyanin, and oxidative stress resistance against all the strains. Amlodipine exhibited the most potent antimicrobial activity with MIC in the range of 6.25 to 25 µg/ml. Significant inhibition in biofilm production was seen in the range of 45.75 to 76.70%. A maximum decrease of 54.66% and 59.45% in swimming and twitching motility was observed, respectively. Maximum inhibition of 65.87% of pyocyanin pigment was observed with the effect of amlodipine. Moreover, a significant decrease in rhamnolipids production observed after amlodipine treatment was between 16.5 and 0.001 mg/ml as compared to the control. All bacterial strains exhibited leakage of proteins and nucleic acids from their cell membranes when exposed to amlodipine which suggests the damage of the structural integrity. In conclusion, amlodipine exhibited good antimicrobial activity and can be used as a potential candidate to be repurposed for the treatment of urinary tract infections.

PMID:40371041 | PMC:PMC12069773 | DOI:10.1007/s12088-024-01280-z

ACS Pharmacol Transl Sci. 2025 Apr 3;8(5):1292-1312. doi: 10.1021/acsptsci.4c00680. eCollection 2025 May 9.

ABSTRACT

Despite the widespread use of selective serotonin reuptake inhibitors like sertraline, the intricate molecular mechanisms underlying major depression and the therapeutic efficacy of these treatments remain not fully elucidated. Building on our preliminary findings, this study investigates the antidepressant effects of fasudil, a Rho-associated protein kinase (ROCK) inhibitor typically utilized as a vasodilator and antispasmodic, and compares its effects with those of sertraline using a chronic restraint stress model in rats. Specifically, we examined the effects of chronic administration on dendritic spine density, key molecular survival pathways, and miRNA levels in the hippocampus. Adult male Sprague-Dawley rats were administered sertraline, fasudil (10 mg/kg/day), or saline over 14 days, with a subset experiencing daily restraint stress. Our findings demonstrate that both sertraline and fasudil effectively prevented stress-induced reductions in dendritic spine density and miR-138 levels in the rat hippocampus. Additionally, by employing a network pharmacology approach, we explored the converging molecular pathways influenced by both drugs, facilitating the identification of novel molecular targets and pathways implicated in the pathophysiology of depression and its treatment. Pharmacoinformatic analysis revealed common signaling cascades and critical proteins that may potentially underlie the observed pharmacological effects, contributing to a paradigm shift in understanding depression by integrating drug repurposing and network pharmacology, offering valuable insights into the underlying mechanisms of depression and the antidepressant effect from a new network-based paradigm rather than focusing solely on a single protein target.

PMID:40370991 | PMC:PMC12070322 | DOI:10.1021/acsptsci.4c00680

Acta Pharm Sin B. 2025 Mar;15(3):1680-1695. doi: 10.1016/j.apsb.2025.01.022. Epub 2025 Feb 12.

ABSTRACT

Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity, expanding antibacterial spectra, and reducing required dosages. Previously, compound 15 was identified as a potential adjuvant for Polymyxin B (PB) against multidrug-resistant (MDR) Pseudomonas aeruginosa DK2; however, its clinical utility was hindered by high cytotoxicity, uncertain in vivo efficacy, and an unclear synergetic mechanism. To address these challenges, we synthesized and evaluated a series of novel benzamide derivatives, with A22 emerging as a particularly promising candidate. A22 demonstrated potent synergistic activity to PB, minimal cytotoxicity, improved water solubility, and broad-spectrum synergism of polymyxins against various clinically isolated MDR Gram-negative strains. In vivo studies using Caenorhabditis elegans and mouse models further confirmed the efficacy of A22. Moreover, A22 effectively suppressed the development of PB resistance in Pseudomonas aeruginosa DK2. Mechanistic investigations revealed that A22 enhances polymyxins activity by inducing reactive oxygen species production, reducing ATP levels, increasing NOX activity, and inhibiting biofilm formation, leading to bacterial death. These findings position A22 as a highly promising candidate for the development of polymyxin adjuvants, offering a robust approach to combating MDR Gram-negative bacterial infections.

PMID:40370545 | PMC:PMC12069892 | DOI:10.1016/j.apsb.2025.01.022

J Cereb Blood Flow Metab. 2025 May 15:271678X251340234. doi: 10.1177/0271678X251340234. Online ahead of print.

ABSTRACT

Neuroprotection after ischemic stroke has been focused on targeting one pathway of the ischemic cascade. In this study, we have hypothesized that combination therapy with alpha-1 antitrypsin (A1AT) and a blocker of tumor necrosis factor (TNFα) could be beneficial in the acute phases after ischemia. Following a detailed safety assessment of the co-administration of both drugs, we tested their neuroprotective effect in a transient mouse model of proximal middle cerebral artery occlusion (MCAo) by evaluating infarct extension and functional outcomes. Anti-TNFα (20 mg/kg) and A1AT were administered at different doses (ranging from 60 mg/kg to 700 mg/kg), as a single therapy during occlusion or at different time-points following reperfusion. Results showed that the administration of A1AT (60 mg/kg) in combination with anti-TNFα (20 mg/kg) was safe and effective when given during occlusion by reducing infarct volume at 24 h by 27% compared with the vehicle group (p = 0.0001). In conclusion, the synergy of the anti-apoptotic and anti-inflammatory properties of both drugs can reduce infarct volume in a stroke mouse model when given in the hyperacute phase. This approach shows promise as an early intervention strategy for stroke patients and underscores the potential of drug repurposing to develop new stroke treatments.

PMID:40370316 | DOI:10.1177/0271678X251340234

J Transl Med. 2025 May 14;23(1):543. doi: 10.1186/s12967-025-06491-6.

ABSTRACT

BACKGROUND: Genome-wide association studies (GWAS) and subsequent functional interpretation have been used to identify susceptible genes and potential drug-repositioning candidates. This study aimed to identify genes associated with colorectal cancer (CRC) and potential drug-repositioning candidates.

METHODS: Patients with CRC at Seoul National University Hospital (SNUH, discovery study) and Chonnam National University Hospital (CNUH, replication study) were included as case groups. The Korean Genome and Epidemiology Study (KoGES) participants were included as a control group. Single-nucleotide polymorphisms (SNPs) were extracted from blood-derived DNA (N = 409,063). A SNP-based logistic regression model was applied. Furthermore, post-GWAS analysis was conducted. Drug-repositioning candidates were identified using a pre-trained deep neural network and the druggability assessment tool.

RESULTS: In the discovery study, we conducted a 1:3 age- and sex-matched case-control study that included 500 CRC cases (mean age 63.0 ± 7.15 years) and 1,500 healthy controls (mean age 62.9 ± 7.07 years), each group comprising 50% males and 50% females. The replication study enrolled 4,860 patients with CRC and 46,384 healthy controls. The two-stage GWAS revealed statistically significant associations among MKLN1 (rs75170436, 7q32.3, beta (log odds ratio) = - 0.90, Pmeta = 5.90 × 10-13), MMP14 (rs3751489, 14q11.2, beta (log odds ratio) = - 1.91, Pmeta = 2.31 × 10-12). Post-GWAS functional analysis revealed strong associations on two genes highlighting deleterious effects and increased gene expression. Drug-repositioning analysis identified GW0742 (PPARβ/δ agonist) with the highest binding score and druggability score for MMP14 with a reference allele (12.06, 0.85).

CONCLUSIONS: Using GWAS, MKLN1 and MMP14 were found to be associated with CRC development and we identified GW0742 (PPARβ/δ agonist) as a potential drug-repositioning candidate for CRC based on MKLN1 and MMP14. These findings improve the understanding of CRC development and provide insights into novel therapeutic targets and candidates for CRC treatment.

PMID:40369569 | DOI:10.1186/s12967-025-06491-6

Hematol Oncol Clin North Am. 2025 May 13:S0889-8588(25)00046-2. doi: 10.1016/j.hoc.2025.04.008. Online ahead of print.

ABSTRACT

Ultra-rare sarcomas are sarcomas with an incidence of 1 case per million inhabitants per year, in which rarity poses a barrier to conducting histotype-specific randomized studies. This manuscript provides practical information and reference for clinicians and researchers looking to develop an understanding of the complexity, worldwide discrepancies in treatment options, and management choices for these patients. We provide definitions, diagnostic challenges, and therapeutic approaches to ultra-rare sarcomas. We highlight existing discriminations faced by patients with ultra-rare sarcoma, differences in approval status for innovative agents, and future perspectives for sarcoma experts who aim at working for a change in the field.

PMID:40368740 | DOI:10.1016/j.hoc.2025.04.008

PLoS One. 2025 May 14;20(5):e0323597. doi: 10.1371/journal.pone.0323597. eCollection 2025.

ABSTRACT

Kawasaki disease (KD) is an acute vasculitis that primarily affects children under five and is a leading cause of acquired heart disease in this age group. Despite the standard treatment with intravenous immunoglobulin (IVIG), approximately 10-20% of patients exhibit IVIG resistance, leading to persistent inflammation and an increased risk of coronary artery aneurysms（CAA）. The underlying molecular mechanisms driving KD, particularly the role of pyroptosis, remain incompletely understood. In this study, we employed integrative bioinformatics approaches to investigate the mechanistic role of pyroptosis in KD. By analyzing transcriptomic datasets, we identified differentially expressed genes (DEGs) associated with pyroptosis and immune dysregulation. Weighted Gene Co-Expression Network Analysis (WGCNA) was utilized to uncover key co-expressed gene modules, followed by functional enrichment analyses to explore the biological significance of these genes. Through machine learning-based biomarker discovery, we identified MYD88 and S100A12 as critical pyroptosis-related genes in KD. Their diagnostic potential was validated using external datasets, and their involvement in immune cell infiltration was assessed through computational deconvolution techniques. Furthermore, drug repurposing analysis and molecular docking simulations suggested that Atogepant, Ubrogepant, and Zanubrutinib could serve as potential therapeutic candidates targeting S100A12 and MYD88. These findings provide novel insights into the molecular pathogenesis of KD and highlight potential biomarkers and therapeutic targets for improving KD diagnosis and treatment strategies.

PMID:40367231 | DOI:10.1371/journal.pone.0323597

JAMA Psychiatry. 2025 May 14. doi: 10.1001/jamapsychiatry.2025.0900. Online ahead of print.

NO ABSTRACT

PMID:40366672 | DOI:10.1001/jamapsychiatry.2025.0900

Molecules. 2025 Apr 24;30(9):1897. doi: 10.3390/molecules30091897.

ABSTRACT

Crohn's disease is an inflammatory bowel disease (IBD) that currently lacks satisfactory treatment options. Therefore, new targets for new drugs are urgently needed to combat this disease. In the present study, we investigated the transcriptomics-based mRNA expression of intestinal biopsies from patients with Crohn's disease. We compared the mRNA expression profiles of the ileum and colon of patients with those of healthy individuals. A total of 72 genes in the ileum and 33 genes in the colon were differentially regulated. Among these, six genes were overexpressed in both tissues, including IL1B, TCL1A, HCAR3, IGHG1, S100AB, and OSM. We further focused on OSM/oncostatin M. To confirm the responsiveness of intestinal tissues from patients with Crohn's disease to oncostatin M inhibition, we examined the expression of the oncostatin M using immunohistochemistry in patient biopsies as well as in kindlin-1-/- and kindlin-2-/- knockout mice, which exhibit an inflammatory bowel disease (IBD) phenotype, and found strong oncostatin M expression in all samples examined. Next, we conducted a drug-repurposing study using the supercomputer MOGON and bioinformatic methods. A total of 13 candidate compounds out of 1577 FDA-approved drugs were identified by PyRx-based virtual drug screening and AutoDock-based molecular docking. Their lowest binding energies (LBEs) ranged from -10.46 (±0.08) to -8.77 (±0.08) kcal/mol, and their predicted inhibition constants (pKi) ranged from 21.62 (±2.97) to 373.78 (±36.78) nM. Ecamsule has an interesting stereostructure with two C2-symmetric enantiomers (1S,4R-1'S,4'R and 1R,4S-1'R,4'S) (1a and 1b) and one meso diastereomer (1S,4R-1'R,4'S) (1c). These three stereoisomers showed strong, albeit differing, binding affinities in molecular docking. As examined by nuclear magnetic resonance and polarimetry, the 1S,4R-1'S,4'R isomer was the stereoisomer present in our commercially available preparations used for microscale thermophoresis. Ecamsule (1a) was chosen for in vitro validation using recombinant oncostatin M and microscale thermophoresis. Considerable dissociation constants were obtained for ecamsule after three repetitions with a Kd value of 11.36 ± 2.83 µM. Subsequently, we evaluated, by qRT-PCR, the efficacy of ecamsule (1a) as a potential drug that could prevent oncostatin M activation by inhibiting downstream inflammatory marker genes (IL6, TNFA, and CXCL11). In conclusion, we have identified oncostatin M as a promising new drug target for Crohn's disease through transcriptomics and ecamsule as a potential new drug candidate for Crohn's disease through a drug-repurposing approach both in silico and in vitro.

PMID:40363705 | DOI:10.3390/molecules30091897

Int J Mol Sci. 2025 May 7;26(9):4453. doi: 10.3390/ijms26094453.

ABSTRACT

Parkinson's disease (PD) is a complex neurodegenerative disorder lacking effective disease-modifying treatments. In this study, we integrated large-scale protein-protein interaction networks with a multi-modal graph neural network (GNN) to identify and prioritize multi-target drug repurposing candidates for PD. Network analysis and advanced clustering methods delineated functional modules, and a novel Functional Centrality Index was employed to pinpoint key nodes within the PD interactome. The GNN model, incorporating molecular descriptors, network topology, and uncertainty quantification, predicted candidate drugs that simultaneously target critical proteins implicated in lysosomal dysfunction, mitochondrial impairment, synaptic disruption, and neuroinflammation. Among the top hits were compounds such as dithiazanine, ceftolozane, DL-α-tocopherol, bromisoval, imidurea, medronic acid, and modufolin. These findings provide mechanistic insights into PD pathology and demonstrate that a polypharmacology approach can reveal repurposing opportunities for existing drugs. Our results highlight the potential of network-based deep learning frameworks to accelerate the discovery of multi-target therapies for PD and other multifactorial neurodegenerative diseases.

PMID:40362692 | DOI:10.3390/ijms26094453

Int J Mol Sci. 2025 Apr 25;26(9):4079. doi: 10.3390/ijms26094079.

ABSTRACT

Thiol-containing drugs may interact with a region of tropomyosin receptor kinase A (TrkA), potentially inhibiting its activation by nerve growth factor (NGF). This action has been linked to potential analgesic activities. Here, we describe the ability of erdosteine, a thiolic compound classified as a mucolytic agent, to bind to the TrkA receptor sequence in silico and its in vitro effects on TrkA activation induced by NGF in cultured human neuroblastoma cells. Our results show that erdosteine and its metabolite, Met-1, bind to the TrkA receptor pocket, involving the primary TrkA residues Glu331, Arg347, His298, and His297. Furthermore, Met-1 has the ability to reduce the disulfide bridge between Cys300 and Cys345 of TrkA. In vitro measurement of TrkA autophosphorylation following NGF activation confirmed that erdosteine and Met-1 interfere with NGF-induced TrkA activation, leading to a consequent loss of the molecular recognition and spatial reorganization necessary for the induction of the autophosphorylation process. This effect was inhibited by low millimolar concentrations of the two compounds, reaching a maximal inhibition (around 40%) after 24 h of exposure to 1 mM erdosteine, and then plateauing. These findings suggest that erdosteine can act as a TrkA antagonist, thus indicating that this drug may have potential as an analgesic via a novel non-opioid mechanism of action operating through NGF signaling inhibition at the level of TrkA.

PMID:40362318 | DOI:10.3390/ijms26094079

Int J Mol Sci. 2025 Apr 22;26(9):3936. doi: 10.3390/ijms26093936.

ABSTRACT

The high heterogeneity between patients can complicate the diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we explored the association of universally differentially expressed genes (UDEGs) with resistance to chemotherapy and immunotherapy in the context of pancreatic cancer. In this work, sixteen up-regulated and three down-regulated genes that were dysregulated in more than 85% of 102 paired and 5% of 521 unpaired PDAC samples were identified and defined as UDEGs. A single-cell level analysis further validated the high expression levels of the up-UDEGs and the low levels of the down-UDEGs in cancer-related ductal cells, which could represent the malignant changes seen in pancreatic cancer. Based on a drug sensitivity analysis, we found that ANLN, GPRC5A and SERPINB5 are closely related to the resistance mechanism of PDAC, and their high expression predicted worse survival for PDAC patients. This suggests that targeting these genes could be a potential way to reduce drug resistance and improve survival. Based on the immune infiltration analysis, the abnormal expression of the UDEGs was found to be related to the formation of an immunosuppressive tumor microenvironment. In conclusion, these UDEGs are common features of PDAC and could be involved in the resistance of pancreatic cancer and might serve as novel drug targets to guide research into drug repurposing.

PMID:40362181 | DOI:10.3390/ijms26093936

Cancers (Basel). 2025 Apr 27;17(9):1470. doi: 10.3390/cancers17091470.

ABSTRACT

BACKGROUND/OBJECTIVES: Colorectal cancer (CRC) is a significant global health issue with rising incidence and mortality rates. In oncology, drug repurposing has emerged as a promising therapeutic strategy in conjunction with conventional treatments. This study aimed to evaluate the potential of repurposing propranolol (PRO), a beta blocker, for the treatment of CRC cell lines (HCT-116 and HT-29), both as a monotherapy and in combination with capecitabine (CAP).

METHODS: Effects of mono- and combination therapies on viability, combination index, morphology, and cell death induction of CRC cells were assessed. Transcriptome analysis of HT-29 cells was performed using RNA sequencing. Metabolite profiling was conducted, and changes in biochemical parameters were evaluated using flow cytometry and biochemical analyses.

RESULTS: The combination index showed that HT-29 cells were the most responsive to the combined treatment, even with PIK3CA, B-RAF (V600E), and TP53 mutations. Moreover, ferroptosis was synergistically activated in the combined group of HT-29 in comparison to control. Furthermore, we observed an increase in OXPHOS metabolites, along with elevated intracellular and mitochondrial ROS, disruption of mitochondrial membrane potential, and greater levels of malondialdehyde (MDA) in the HT-29 combined group, which are the features of ferroptosis. Furthermore, ferroptosis induction was coupled with necroptosis, as indicated by RNA-sequencing data. Combination therapy inhibited cell migration and enhanced the immune response of HT-29 cells.

CONCLUSIONS: These findings suggest that PRO is promising as a potential adjuvant therapy in combination with CAP for the treatment of CRC. Only HT-29 cells with the B-RAF (V600E) mutation showed promising findings in this study.

PMID:40361395 | DOI:10.3390/cancers17091470

Cancers (Basel). 2025 Apr 24;17(9):1430. doi: 10.3390/cancers17091430.

ABSTRACT

Background: Chronic nicotine exposure drives head and neck cancer (HNC) progression, yet its molecular mechanisms remain underexplored. This study examines nicotine-induced transcriptomic changes and potential therapies via drug repurposing. Methods: HNC cell lines (OECM1, SAS, and CGHNC9) were exposed to an IC30 nicotine dose for three months to model chronic exposure in habitual smokers. Transcriptomic profiling of these sublines was integrated with TCGA-HNSC patient data. Differentially expressed genes (DEGs) underwent functional pathway enrichment analysis. Drug repurposing was conducted using gene-drug correlation analysis across GDSC, CTRP, and PRISM databases. Results: Transcriptomic analysis identified 1223 DEGs in nicotine-exposed HNC cells, and integration with TCGA-HNSC data defined a Nic-HNC gene set of 168 genes: 149 oncogenes and 19 tumor suppressors, with 36 oncogenes overexpressed in heavy smokers. Pathway analysis revealed the upregulation of oncogenic signaling, such as PI3K-AKT, alongside the suppression of immune regulation and metabolic reprogramming. Drug repurposing identified five compounds-AZD1332, JAK-8517, NU7441, BRD-K30748066, and neopeltolide-with the first two exhibiting the strongest inverse correlations with nicotine-induced oncogenes in heavy smokers, highlighting their potential as targeted therapies for tobacco-associated HNC. Conclusions: This study comprehensively characterizes nicotine-driven molecular dysregulation in HNC and proposes AZD1332 and JAK-8517 as promising therapeutic candidates through drug repurposing. These insights advance our understanding of nicotine's oncogenic role and provide a foundation for translational research to develop targeted interventions for tobacco-associated HNC.

PMID:40361356 | DOI:10.3390/cancers17091430