Pharmaceutics. 2025 Mar 26;17(4):419. doi: 10.3390/pharmaceutics17040419.

ABSTRACT

In the original publication [...].

PMID:40284534 | DOI:10.3390/pharmaceutics17040419

Pharmaceutics. 2025 Apr 19;17(4):536. doi: 10.3390/pharmaceutics17040536.

ABSTRACT

Background/Objectives: Ovarian cancer remains one of the most commonly diagnosed malignancies among women worldwide. The heterogeneity among tumor subtypes and the emergence of treatment resistance have raised significant concerns regarding the long-term efficacy of chemotherapy, radiotherapy, and immunotherapy. In response to these challenges, drug repurposing strategies-utilizing existing drugs in novel therapeutic contexts-have gained increasing attention. This study aimed to investigate the cytotoxic and apoptotic effects of the combined application of doxorubicin (DX) and thymoquinone (TQ) on ovarian adenocarcinoma cells (OVCAR3). Methods: OVCAR3 cells were cultured in RPMI medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin. Cell viability and proliferation were assessed using the MTT assay following treatment with various concentrations of DX and TQ. NucBlue immunofluorescence staining was employed to examine nuclear morphology and to identify apoptosis-associated changes. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was per-formed to evaluate the expression levels of apoptosis-related and oncogenic pathway genes, including RAF, RAS, Bcl-2, and Bax. Results: The results demonstrated that the combination of DX and TQ significantly reduced OVCAR3 cell viability and induced apoptosis in a dose-dependent manner. qRT-PCR analysis revealed a downregulation of RAS, RAF, and Bcl-2 expression, along with an upregulation of Bax, indicating activation of the intrinsic apoptotic pathway. These findings suggest that thymoquinone exerts an-ti-proliferative and pro-apoptotic effects by modulating the RAS/RAF signaling cascade. Furthermore, the co-administration of thymoquinone with doxorubicin potentiated these effects, suggesting a synergistic interaction between the two agents. Conclusions: Histopathological and molecular evaluations further confirmed the activation of apoptosis and the suppression of key oncogenic pathways. Collectively, these results underscore the therapeutic potential of thymoquinone as both a monotherapy and an adjuvant to conventional chemotherapy, warranting further validation in preclinical and clinical studies.

PMID:40284530 | DOI:10.3390/pharmaceutics17040536

Int J Environ Res Public Health. 2025 Mar 21;22(4):464. doi: 10.3390/ijerph22040464.

ABSTRACT

Data-driven approaches to clinical research are necessary for understanding and effectively treating infectious diseases. However, challenges such as issues with data validity, lack of collaboration, and difficult-to-treat infectious diseases (e.g., those that are rare or newly emerging) hinder research. Prioritizing innovative methods to facilitate the continued use of data generated during routine clinical care for research, but in an organized, accelerated, and shared manner, is crucial. This study investigates the potential of CURE ID, an open-source platform to accelerate drug-repurposing research for difficult-to-treat diseases, with COVID-19 as a use case. Data from eight US health systems were analyzed using least absolute shrinkage and selection operator (LASSO) regression to identify key predictors of 28-day all-cause mortality in COVID-19 patients, including demographics, comorbidities, treatments, and laboratory measurements captured during the first two days of hospitalization. Key findings indicate that age, laboratory measures, severity of illness indicators, oxygen support administration, and comorbidities significantly influenced all-cause 28-day mortality, aligning with previous studies. This work underscores the value of collaborative repositories like CURE ID in providing robust datasets for prognostic research and the importance of factor selection in identifying key variables, helping to streamline future research and drug-repurposing efforts.

PMID:40283693 | DOI:10.3390/ijerph22040464

J Clin Med. 2025 Apr 14;14(8):2673. doi: 10.3390/jcm14082673.

ABSTRACT

Epilepsy is a neurological disorder characterized by repeated convulsions. Antiepileptic drugs (AEDs) are the main course of therapy for epilepsy. These medications are given according to each patient's personal medical history and the types of seizures they suffer. They have been employed for decades to manage epilepsy, thus delivering relief from seizures through numerous mechanisms of action. Aside from their anticonvulsant attributes, current evidence suggests that certain AEDs may display potential inhibitory effects against cancer invasion and metastasis. This review explored the complicated interactions between the modes of action of AEDs and the pathways causing cancer, and the potential impact of AEDs on the invasion and metastasis of various forms of cancer, while addressing their associated side effects. For example, valproic acid inhibits histone deacetylase, causing hyperacetylation of genes, especially those regulating cell cycle, culminating in cell cycle arrest. Topiramate inhibits carbonic anhydrase, thus disrupting the acidic microenvironment needed for cancer cells to thrive. Lacosamide increases the slow inactivation of the voltage gated Na+ channel, thus inhibiting the growth, proliferation, and metastasis of many cancers. Although drug development is a complex task due to regulatory, intellectual property, and economic challenges, researchers are exploring drug repurposing tactics to overcome these challenges and to find new therapeutic alternatives for diseases like cancer. Thus, drug repurposing is considered among the most effective ways to develop drug candidates using novel properties and therapeutic characteristics, and this review also discusses these issues.

PMID:40283503 | DOI:10.3390/jcm14082673

Cancers (Basel). 2025 Apr 18;17(8):1357. doi: 10.3390/cancers17081357.

ABSTRACT

BACKGROUND/OBJECTIVES: Beta adrenergic signaling has been implicated in cancer progression, leading to interest in repurposing beta blockers (BBs) as adjunctive anti-cancer agents. However, clinical findings are inconsistent. This systematic review and meta-analysis evaluates the association between BB use and survival outcomes in cancer patients.

METHODS: A systematic search of OVID Medline, EMBASE, and CENTRAL was conducted through 13 September 2023, for studies comparing survival outcomes in solid tumor patients using BBs versus non-users. Eligible studies reported hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), or cancer-specific survival (CSS). Perioperative studies and those without BB-specific HRs were excluded. Data extraction and quality assessment were performed in duplicate using ROBINS-I. A random-effects model was used, with heterogeneity assessed by the I2 statistic.

RESULTS: Seventy-nine studies (492,381 patients) met the inclusion criteria; 2.5% were prospective. The most frequently studied cancers were breast (n = 33), ovarian (n = 30), and colorectal (n = 28). BB use was associated with improved PFS (HR 0.78, 95% CI: 0.66-0.92, I2 = 79.8%), with significance maintained after excluding high-bias studies (HR 0.74, 95% CI: 0.61-0.91, I2 = 36.6%). No significant associations were observed for OS (HR 0.99, 95% CI: 0.94-1.04, I2 = 84.9%) or CSS (HR 0.95, 95% CI: 0.91-1.00, I2 = 77.4%).

CONCLUSIONS: BB use may be associated with longer PFS in cancer patients, but findings are limited by study design and heterogeneity; high-quality prospective studies are needed.

PMID:40282534 | DOI:10.3390/cancers17081357

Eur J Paediatr Neurol. 2025 Apr 15;56:46-50. doi: 10.1016/j.ejpn.2025.03.016. Online ahead of print.

ABSTRACT

Leukodystrophies, a group of genetic disorders primarily affecting brain white matter, were once considered untreatable. Advances in MRI and genetic diagnostics now allow most patients to receive a genetic diagnosis, and emerging treatments are shifting the field from therapeutic nihilism to cautious optimism. Allogenic haematopoietic stem cell transplantation (HSCT), used since the 1980s, has shown efficacy in specific leukodystrophies, such as adrenoleukodystrophy and metachromatic leukodystrophy, when administered early. Gene therapy has become a viable option, with ex vivo approaches like atidarsagene autotemcel providing promising outcomes for early-onset MLD. Trials for gene replacement and antisense oligonucleotide therapies are ongoing for several leukodystrophies, including Canavan disease and Alexander disease. Certain treatments, such as guanabenz for Vanishing White Matter, target disease-specific dysregulated molecular pathways. Despite these advances, challenges remain, including the ultrarare nature of most leukodystrophies, limited natural history data, high treatment costs, and barriers to accessibility. Future developments, including newborn screening and close international collaboration, aim to enhance early diagnosis, refine treatment timing, and expand access to innovative therapies.

PMID:40279833 | DOI:10.1016/j.ejpn.2025.03.016

Sci Data. 2025 Apr 25;12(1):695. doi: 10.1038/s41597-025-04981-2.

ABSTRACT

Drug-target interactions constitute the fundamental basis for understanding drug action mechanisms and advancing therapeutic discovery. While existing drug-target databases have contributed valuable resources, they exhibit structural and functional fragmentation due to heterogeneous data sources and annotation standards. Building upon the high-confidence drug-gene interactions curated in HCDT 1.0, we present HCDT 2.0, a comprehensive and standardized resource that expands the scope through multiomics data integration. This update incorporates three-dimensional interactions including drug-gene, drug-RNA and drug-pathway interactions. The current version contains 1,284,353 curated interactions: 1,224,774 drug-gene pairs (678,564 drugs × 5,692 genes), 11,770 drug-RNA mappings (316 drugs × 6,430 RNAs), and 47,809 drug-pathway links (6,290 drugs × 3,143 pathways), alongside 16,317 drug-disease associations. To enhance biological interpretability, we further integrated pathway-gene and RNA-gene regulatory relationships. In addition, we integrated 38,653 negative DTIs covering 26,989 drugs and 1,575 genes. This integrative framework not only addresses critical gaps in cross-scale data representation but also establishes a robust foundation for systems pharmacology applications, including drug repurposing, adverse event prediction, and precision oncology strategies.

PMID:40281032 | DOI:10.1038/s41597-025-04981-2

Acta Neuropathol Commun. 2025 Apr 25;13(1):84. doi: 10.1186/s40478-025-01986-1.

ABSTRACT

Prolactinoma is the most prevalent pituitary neuroendocrine tumor and dopamine agonists (DAs) targeting dopamine D2 receptor (DRD2) are recommended as the first-line treatment. However, varying degrees of DA resistance limit patient benefit. Our study used transcriptome sequencing of surgical tumor samples and found abnormal cholesterol metabolism in prolactinoma, especially in DA-resistant tumors. We found that cholesterol significantly enhanced the resistance of prolactinoma MMQ cell lines to cabergoline in vitro and in vivo xenografts. Further, cholesterol did not affect the total protein level of DRD2, but changed the distribution of DRD2 with downregulation of its membrane abundance and upregulation of cytoplasmic localization. Mechanistically, immunoprecipitation combined with mass spectrometry revealed cholesterol increased binding affinity between DRD2 and stress granules (SGs) core proteins, such as G3BP1. Western blot experiment of G3BP1 and fluorescent probe were used to confirm the formation of SGs after cholesterol treatment in MMQ cells and tumor xenografts, as well as in surgical tumor samples. Interfering the formation of SGs by overexpressing of USP10 and using the small molecule ISRIB reversed cholesterol's effect on DRD2 cellular distribution and DA resistance in MMQ cells. Finally, a non-specificity inhibitor of SGs, anisomycin identified by drug repositioning analysis, could attenuate cholesterol-induced cabergoline resistance in vitro. Taken together, our findings suggest that abnormal cholesterol metabolism reduces DRD2 membrane localization via stress granules formation, which may be an important reason for the DA resistance of prolactinoma patients.

PMID:40281543 | DOI:10.1186/s40478-025-01986-1

Sci Rep. 2025 Apr 25;15(1):14436. doi: 10.1038/s41598-025-98894-0.

ABSTRACT

Extracellular vesicles (EVs) are important mediators of intercellular communication and play key roles in the regulation of pathophysiological processes. In diabetic kidney disease (DKD), it has been reported that macrophages recruited in the mesangial region may play pathogenic roles through inducing local inflammation in glomeruli. We focused on EV-mediated crosstalk between mesangial cells (MC) and macrophages as a novel therapeutic target for DKD. EVs released from MC induced inflammation in macrophages and the effect was enhanced under high-glucose conditions. For discovering novel therapeutic agents which can inhibit such EV-mediated mechanisms, drug repositioning is considered as an effective tool. We established a unique screening strategy and screened agents to aim at maximizing their specificity and potency to inhibit EV mechanisms, along with minimizing their toxicity. We succeeded in identifying alvespimycin, an HSP90 inhibitor. Treatment of diabetic rats with alvespimycin significantly suppressed mesangial expansion, inflammatory gene activation including macrophage markers, and proteinuria. The inhibitory effect on EV uptake was specific to alvespimycin compared with other known HSP90 inhibitors. MC-derived EVs are crucial for inflammation by intercellular crosstalk between MC and macrophages in DKD, and alvespimycin effectively ameliorated the progression of DKD by suppressing EV-mediated actions, suggesting that EV-targeted agents can be a novel therapeutic strategy.

PMID:40281012 | DOI:10.1038/s41598-025-98894-0

Biomed Pharmacother. 2025 Apr 24;187:118079. doi: 10.1016/j.biopha.2025.118079. Online ahead of print.

ABSTRACT

This study investigated a novel immunization therapy for pre-clinical aggressive metastatic breast cancer using immunogenic cell lysates derived from 4T1-luc cells treated with cisplatin and methotrexate, addressing the critical need for improved treatments given the poor prognosis associated with breast cancer metastasis and its significant mortality rate. Methotrexate, a conventional cytotoxic agent, demonstrated a previously unrecognized capacity to induce immunogenic cell lysates, presenting a potential drug repositioning opportunity. In a murine model of stage IV metastatic breast cancer, immunization with these lysates significantly reduced primary tumor growth and lung metastasis, as assessed by bioluminescence imaging. Immunization also modulated immune cell populations, reducing splenomegaly and hepatomegaly, and partially reversing the immunosuppressive phenotype associated with 4T1-luc tumor growth, as evidenced by cytokine profiling (IL-6 and IFN-γ) and flow cytometry analysis of CD4 + and CD8 + T cell subpopulations. Specifically, methotrexate-treated lysates induced a significant shift in CD4 + T cells towards an effector phenotype. These findings highlight the potential of this immunotherapy approach to improve breast cancer treatment outcomes and warrant further investigation.

PMID:40280032 | DOI:10.1016/j.biopha.2025.118079

IEEE J Biomed Health Inform. 2025 Apr 25;PP. doi: 10.1109/JBHI.2025.3564360. Online ahead of print.

ABSTRACT

Drug repositioning (DR) has emerged as an effective method of identifying new indications for existing drugs. Many DR methods have demonstrated superior performance. However, most of them utilize a limited number of biological entities, ignoring the critical role of other entities in addressing data sparsity as well as improving model generalization capabilities. In addition, fully capturing high-order information of biological data still needs to be fully explored. To address above issues, a model based on transformer and enhanced multi-view contrastive learning (TEMCL) is proposed for predicting drug-disease associations (DDAs). Firstly, transformer is employed to obtain high-order features of nodes from similarity information. Secondly, based on similarity matrices and association matrices of nodes, two different types of views are constructed, i.e., homogeneous hypergraphs and heterogeneous association graphs. Among them, to alleviate sparsity problem existing in heterogeneous graphs, protein nodes as well as meta-path enhancement strategy are introduced. Thirdly, hypergraph convolutional network and heterogeneous graph transformer are used to extract node features on above two types of views, respectively. Contrastive learning is applied to obtain more representative features. Finally, multilayer perceptron (MLP) is used for predicting DDAs. Experiments show that TEMCL outperforms existing methods on DR task, exhibiting superior performance. In addition, case studies further demonstrate the effectiveness of this model. TEMCL provides new insights for identifying novel DDAs.

PMID:40279215 | DOI:10.1109/JBHI.2025.3564360

Adv Exp Med Biol. 2025 Apr 26. doi: 10.1007/5584_2025_863. Online ahead of print.

ABSTRACT

Despite advances in cancer research, treating malignancies remains challenging due to issues like drug resistance, disease heterogeneity, and the limited efficacy of current therapies, particularly in relapsed or refractory cases. In recent years, several drugs originally approved for non-cancer indications have shown potential in cancer treatment, demonstrating anti-proliferative, anti-metastatic, and immunomodulatory effects. Drug repurposing has shown immense promise due to well-established safety profiles and mechanisms of action of the compounds. However, the implementation is fraught with clinical, logistical, regulatory, and ethical challenges, especially in diseases such as leukaemia and multiple myeloma. This chapter examines the treatment challenges in leukaemia and multiple myeloma, focusing on the role of drug repurposing in addressing therapeutic resistance and disease variability. It highlights the potential of personalized, tailored combination therapies, using repurposed drug components, to offer more effective, targeted, and cost-efficient treatment strategies, overcoming resistance and improving patient outcomes.

PMID:40279000 | DOI:10.1007/5584_2025_863

Neurochem Res. 2025 Apr 25;50(3):154. doi: 10.1007/s11064-025-04404-z.

ABSTRACT

Parkinson's disease (PD) is one of neurodegenerative diseases characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The development of a neuroprotective therapy is crucial for mitigating features and progression of PD. Since autophagy induction has recently emerged as a promising neuroprotective strategy, this study aimed to identify autophagy-inducing compounds and evaluate their neuroprotective activity. Among 3,200 compounds consisting of FDA-approved drugs or are under active development, 547 compounds targeting neurological diseases were filtered in, and three compounds (sertraline, tiagabine and bicifadine) were finally identified to exhibit the autophagy-inducing activity and also demonstrated the autophagy-dependent neuroprotective action by inhibiting the mammalian target of rapamycin (mTOR) in 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in PC12 cells. Furthermore, the analysis of neurochemical changes suggested that the ability of those compounds to restore the quantity of cellular neurotransmitters such as betaine, 5-hydroxyindoleacetic acid and kynurenine might be linked to their neuroprotective function. In conclusion, compounds like sertraline, tiagabine, and bicifadine that have the ability to induce autophagy and inhibit mTOR might be repurposed as PD treatment to protect the neuronal cells.

PMID:40278973 | DOI:10.1007/s11064-025-04404-z

J Chem Inf Model. 2025 Apr 25. doi: 10.1021/acs.jcim.5c00070. Online ahead of print.

ABSTRACT

The extraction of biomedical data has significant academic and practical value in contemporary biomedical sciences. In recent years, drug repositioning, a cost-effective strategy for drug development by discovering new indications for approved drugs, has gained increasing attention. However, many existing drug repositioning methods focus on mining information from adjacent nodes in biomedical networks without considering the potential inter-relationships between the feature spaces of drugs and diseases. This can lead to inaccurate encoding, resulting in biased mined drug-disease association information. To address this limitation, we propose a new model called Dual-Feature Drug Repurposing Neural Network (DFDRNN). DFDRNN allows the mining of two features (similarity and association) from the drug-disease biomedical networks to encode drugs and diseases. A self-attention mechanism is utilized to extract neighbor feature information. It incorporates two dual-feature extraction modules: the single-domain dual-feature extraction (SDDFE) module for extracting features within a single domain (drugs or diseases) and the cross-domain dual-feature extraction (CDDFE) module for extracting features across domains. By utilizing these modules, we ensure more appropriate encoding of drugs and diseases. A cross-dual-domain decoder is also designed to predict drug-disease associations in both domains. Our proposed DFDRNN model outperforms six state-of-the-art methods on four benchmark data sets, achieving an average AUROC of 0.946 and an average AUPR of 0.597. Case studies on three diseases show that the proposed DFDRNN model can be applied in real-world scenarios, demonstrating its significant potential in drug repositioning.

PMID:40278791 | DOI:10.1021/acs.jcim.5c00070

Metabolites. 2025 Apr 9;15(4):255. doi: 10.3390/metabo15040255.

ABSTRACT

BACKGROUND/OBJECTIVES: Drug development for complex diseases such as NAFLD is often lengthy and expensive. Drug repurposing, the process of finding new therapeutic uses for existing drugs, presents a promising alternative to traditional approaches. This study aims to identify potential repurposed drugs for NAFLD by leveraging disease-disease relationships and drug-target data from the BioSNAP database.

METHODS: A bipartite network was constructed between drugs and their target genes, followed by the application of the BiClusO bi-clustering algorithm to identify high-density clusters. Clusters with significant associations with NAFLD risk genes were considered to predict potential drug candidates. Another set of candidates was determined based on disease similarity.

RESULTS: A novel ranking methodology was developed to evaluate and prioritize these candidates, supported by a comprehensive literature review of their effectiveness in NAFLD treatment.

CONCLUSIONS: This research demonstrates the potential of drug repurposing to accelerate the development of therapies for NAFLD, offering valuable insights into novel treatment strategies for complex diseases.

PMID:40278384 | DOI:10.3390/metabo15040255

Cells. 2025 Apr 11;14(8):575. doi: 10.3390/cells14080575.

ABSTRACT

Lithium is prescribed as a mood stabilizer for bipolar disorder and severe depression. However, the mechanism of action of lithium is unknown and there are major side effects associated with prolonged medication. This motivates a search for safer alternative drug repurposing candidates. Given that the drug mechanism may be encoded in transcriptional changes, we generated the gene expression profile for acute lithium treatment of cortical neuronal cultures. We found that the lithium-associated transcription response harbors a significant component that is the reverse of that seen in human brain samples from patients with major depression, bipolar disorder, and a mouse model of depression. Interrogating publicly available drug-driven expression data, we found that cardiotonic steroids drive gene expression in a correlated manner to our acute lithium profile. An analysis of the psychiatric medication cohort of the Norwegian Prescription Database showed that cardiotonic prescription is associated with a lower incidence of lithium prescription. Our transcriptional and epidemiological observations point towards cardiotonic steroids as possible repurposing candidates for lithium. These observations motivate a controlled trial to establish a causal connection and genuine therapeutic benefit in the context of depression.

PMID:40277900 | DOI:10.3390/cells14080575

Cells. 2025 Apr 8;14(8):559. doi: 10.3390/cells14080559.

ABSTRACT

Rare diseases typically evade the application of the standard drug discovery and development pipelines due to their understudied molecular etiology and the small market size. Herein, we report a rare disease-directed workflow that rapidly studies the molecular features of the disorder, establishes a high-throughput screening (HTS) platform, and conducts an HTS of thousands of approved drugs to identify and validate repositioning drug candidates. This study examines the pediatric neurological disorder caused by de novo mutations in YWHAG, the gene encoding the scaffolding protein 14-3-3γ, and the workflow discovers nuclear relocalization and a severe drop in 14-3-3γ binding to its phosphorylated protein partners as the key molecular features of the pathogenic hotspot YWHAG mutations. We further established a robust in vitro HTS platform and screened ca. 3000 approved drugs to identify the repositioning drug candidates that restore the deficient 14-3-3γ-phosphotarget interactions. Our workflow can be applied to other 14-3-3-related disorders and upscaled for many other rare diseases.

PMID:40277885 | DOI:10.3390/cells14080559

J Helminthol. 2025 Apr 25;99:e55. doi: 10.1017/S0022149X25000276.

ABSTRACT

Benzimidazoles are the most frequently prescribed therapeutic options for treating trichinellosis in clinical settings; however, they have a lot of disadvantages. Therefore, researchers are focusing on the hunt for substitute chemicals. The goal of the current study was to compare the effectiveness of albendazole and the anti-diabetic medication metformin loaded on chitosan nanoparticles in treating mice infected with various stages of T. spiralis infection. 160 mice were included in the present study and divided into 8 groups: 6 experimentally treated groups, and positive and negative control groups. For studying the intestinal and parenteral phase, each group was broken into two more subgroups (a and b) according to the time of drug administration. The effects of albendazole, albendazole-loaded NPs, metformin, metformin-loaded NPs, combined albendazole and metformin, and metformin and albendazole-loaded NPs were assessed using parasitological studies, histopathological examination, and ultrastructural examination using SEM.Statistically significant differences were detected in all studied subgroups compared to the control infected subgroup both in the intestinal and muscular phases. The greatest decrease in recovered adult worm and muscle larvae numbers was achieved by ABZ & MET/ Cs NPs. These findings were confirmed by histopathological examination. SEM examination of the tegument of T. spirals adult worms and muscle larvae showed destruction with multiple degenerative changes.Our results suggested that metformin and its combination with albendazole especially when loaded on chitosan nanoparticles could be potential therapeutic alternative drugs against trichinellosis.

PMID:40275564 | DOI:10.1017/S0022149X25000276

Orphanet J Rare Dis. 2025 Apr 24;20(1):195. doi: 10.1186/s13023-025-03711-6.

ABSTRACT

BACKGROUND: Chanarin-Dorfman syndrome (CDS) is a multisystemic autosomal recessive rare disorder. CDS is caused by variants in the abhydrolase domain containing 5 (ABHD5) encoding gene (CGI-58), which ultimately leads to excessive lipid storage, and therefore a high abundance of cellular lipid droplets (LDs). Although the molecular etiology of the disease was described many years ago, no treatment for CDS is currently available.

RESULTS: To further characterize the molecular basis of the disease and to uncover new treatment avenues, we used skin fibroblasts originating from a young patient diagnosed with CDS due to a homozygous nonsense mutation. We show that dysfunctional ABHD5 does not only affect LDs, but also influences other metabolic-related organelles; the mitochondria and peroxisomes. Additionally, we found that expressing functional ABHD5 in CDS patient cells reduced LD number. Finally, we developed and applied a high content-based drug repurposing screen based on a collection of ∼2500 FDA approved compounds, yielding several compounds that affected LD total area and size.

CONCLUSIONS: Our findings enhance the understanding of the dysfunction underlying CDS and propose new avenues for the treatment of CDS patients.

PMID:40275410 | DOI:10.1186/s13023-025-03711-6

Sci Rep. 2025 Apr 24;15(1):14315. doi: 10.1038/s41598-025-98689-3.

ABSTRACT

Congenital factor (F) VII deficiency is caused by mutations in the F7 gene. The p.Q160R variant manifests with bleeding episodes due to reduced FVII activity and antigen in patient plasma, most likely caused by protein misfolding and intracellular retention. As current replacement therapy is expensive and requires frequent intravenous injections, there is an unmet need for new and less invasive therapeutic strategies. Drug repurposing allows for rapid, more cost-effective discovery and implementation of new treatments, and identification of pharmacological enhancers of FVII variant activity would be of clinical importance. High-throughput screening of > 1800 FDA-approved drugs identified the orally available histone deacetylase inhibitor abexinostat and the inhaled surfactant tyloxapol as enhancers of FVII p.Q160R variant activity. The positive hits were verified in an in vitro cell model transiently expressing wild type or variant FVII and ex vivo in patients' plasma. Both drugs showed a dose-response effect on FVII antigen and activity levels in conditioned cell medium and on FVII activity in patients' plasma. In conclusion, the efficacy of the FDA-approved drugs abexinostat and tyloxapol in enhancing FVII variant activity constitute a proof of principle for high-throughput identification of drugs that may be feasible for novel treatment of FVII deficiency.

PMID:40274887 | DOI:10.1038/s41598-025-98689-3