Redox Biol. 2025 Mar 3:103569. doi: 10.1016/j.redox.2025.103569. Online ahead of print.

ABSTRACT

Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.

PMID:40059038 | DOI:10.1016/j.redox.2025.103569

Biochimie. 2025 Mar 7:S0300-9084(25)00056-2. doi: 10.1016/j.biochi.2025.03.002. Online ahead of print.

ABSTRACT

Metformin, initially prescribed as an oral hypoglycemic medication for type 2 diabetes, has recently gained attention for its potential anticancer effects. Its history dates to 1918, when guanidine, a component of the traditional European herb Galega officinalis, was found to reduce glycemia. This review precisely examines the mechanisms underlying Metformin's anticancer effects across various neoplastic conditions. This investigation explores the complex interactions between metformin and major signaling pathways associated with carcinogenesis, including AMP-activated protein kinase (AMPK), mTOR, and insulin-like growth factor (IGF) pathways. The review emphasizes Metformin's diverse effects on angiogenesis, inflammation, apoptosis, and cellular metabolism in cancer cells. Additionally, new data on metformin's capacity to alter the tumor microenvironment and enhance immune surveillance systems against cancer are examined. The review underscores Metformin's potential for repurposing in oncology, emphasizing its clinical relevance as an adjuvant therapy for various cancers. The review provides insightful information about the complex anticancer mechanisms of metformin by combining data from preclinical and clinical studies. These findings not only broaden our knowledge of the effects of metformin but also open new avenues for oncology research and treatment developments.

PMID:40058683 | DOI:10.1016/j.biochi.2025.03.002

Comput Biol Med. 2025 Mar 6;189:109989. doi: 10.1016/j.compbiomed.2025.109989. Online ahead of print.

ABSTRACT

The Chikungunya virus (CHIKV) represents a significant global health threat, particularly in tropical regions, and no FDA-approved antiviral treatments are currently available. This study investigates the potential of Direct-Acting Antivirals (DAAs) and protease inhibitors (PIs) that have been developed for the hepatitis C virus (HCV) in treating CHIKV. We analyzed the binding of eight HCV DAAs to the nsP2 protease of CHIKV, which is essential for viral replication. Our findings suggest repurposing hepatitis C virus (HCV) antivirals, specifically Simeprevir (SIM) and voxilaprevir (VOX), could be effective against CHIKV. Through computational analyses, we observed their strong binding affinity to CHIKV's nsP2 protease, indicating the promising potential of repositioning these drugs for CHIKV treatment. To validate the results of our computational study, we evaluated the antiviral efficacy of SIM and VOX in vitro, both as monotherapies and in combination with ribavirin (RIBA). Our findings revealed that DAAs exert a multifaced effect by targeting different stages of the CHIKV life cycle. Furthermore, the synergistic effects suggest that combining SIM and VOX with RIBA may provide a more effective therapeutic strategy than using either drug alone. Further research is necessary to optimize treatment protocols and improve outcomes for patients affected by CHIKV.

PMID:40056839 | DOI:10.1016/j.compbiomed.2025.109989

In Silico Pharmacol. 2025 Mar 4;13(1):36. doi: 10.1007/s40203-025-00325-5. eCollection 2025.

ABSTRACT

Tuberculosis (TB), a major global health concern, even after significant advancements in diagnosis and treatment, causing millions of deaths annually and severely impacting the healthcare systems of developing nations. Moreover, the rise of drug-resistant strains further diminishes the efforts made to control the infection and to overcome this scenario, highly effective drugs are required. Identifying new therapeutic uses of existing drugs through drug repurposing can significantly shorten the time and cost. In the current study, using a computational experimental approach, near about 3104 FDA-approved drugs and active pharmaceutical ingredients from Selleckchem database were screened against Enhanced intracellular survival (Eis) protein, responsible for causing drug resistance by inhibiting the aminoglycoside drug activity. Based on the three-level screening and Molecular Mechanics generalized Born surface area (MM/GBSA) scores, five drugs including Isavuconazonium sulfate, Cefotiam Hexetil Hydrochloride, Enzastaurin (LY317615), Salbutamol sulfate (Albuterol), and Osimertinib (AZD9291) were considered as potential Eis inhibitors. The 500 ns MD simulation results revealed that all these Eis-drug complexes are stable, with minor structural arrangements and stable binding patterns. The PCA and FEL analysis also confirmed the structural stability of the complexes. Overall, these drugs displayed promising results as Eis inhibitors, that can be regarded as suitable candidates for experimental validation.

PMID:40051485 | PMC:PMC11880469 | DOI:10.1007/s40203-025-00325-5

Cancer Cell Int. 2025 Mar 6;25(1):79. doi: 10.1186/s12935-025-03712-2.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) poses a significant clinical challenge because of drug resistance, which can adversely impact patient outcomes. Recent research has shown that abnormalities within the tumor microenvironment, especially hyperglycemia, play a crucial role in promoting metastasis and chemoresistance, and thereby determine the overall prognosis of patients with advanced CRC.

METHODS: This study employs data mining and consensus molecular subtype (CMS) techniques to identify pitavastatin and atorvastatin as potential agents for targeting high glucose-induced drug resistance in advanced CRC cells. CRC cells maintained under either low or high glucose conditions were established and utilized to assess the cytotoxic effects of pitavastatin and atorvastatin, both with and without 5-fluorouracil (5-FU). CRC 3D spheroids cultured were also included to demonstrate the anti-drug resistance of pitavastatin and atorvastatin.

RESULTS: A bioinformatics analysis identified pitavastatin and atorvastatin as promising drug candidates. The CMS4 CRC cell line SW480 (SW480-HG) was established and cultured under high glucose conditions to simulate hyperglycemia-induced drug resistance and metastasis in CRC patients. Pitavastatin and atorvastatin could inhibit cell proliferation and 3D spheroid formation of CMS4 CRC cells under high glucose conditions. In addition, both pitavastatin and atorvastatin can synergistically promote the 5-FU-mediated cytotoxic effect and inhibit the growth of 5-FU-resistant CRC cells. Mechanistically, pitavastatin and atorvastatin can induce apoptosis and synergistically promote the 5-FU-mediated cytotoxic effect by activating autophagy, as well as the PERK/ATF4/CHOP signaling pathway while decreasing YAP expression.

CONCLUSION: This study highlights the biomarker-guided precision medicine strategy for drug repurposing. Pitavastatin and atorvastatin could be used to assist in the treatment of advanced CRC, particularly with CMS4 subtype CRC patients who also suffer from hyperglycemia. Pitavastatin, with an achievable dosage used for clinical interventions, is highly recommended for a novel CRC therapeutic strategy.

PMID:40050889 | DOI:10.1186/s12935-025-03712-2

BMC Cancer. 2025 Mar 6;25(1):412. doi: 10.1186/s12885-025-13733-9.

ABSTRACT

BACKGROUND: Targeting mitochondrial dynamics offers promising strategies for treating glioblastoma multiforme. Celastrol has demonstrated therapeutic effects on various cancers, but its impact on mitochondrial dynamics in glioblastoma multiforme remains largely unknown. We studied the effects of Celastrol on mitochondrial dynamics, redox homeostasis, and the proliferation.

METHODS: Mito-Tracker Green staining was conducted on U251, LN229, and U87-MG cells to evaluate the effects of Celastrol on mitochondrial dynamics. The Western blot analysis quantified the expression levels of mitochondrial dynamin, antioxidant enzymes, and cell cycle-related proteins. JC-1 staining was performed to discern mitochondrial membrane potential. Mitochondrial reactive oxygen species were identified using MitoSOX. The proliferative capacity of cells was assessed using Cell Counting Kit-8 analysis, and colony formation assays. Survival analysis was employed to evaluate the therapeutic efficacy of Celastrol in C57BL/6J mice with glioblastoma.

RESULTS: Our findings suggest that Celastrol (1 and 1.5 µM) promotes mitochondrial fission by downregulating the expression of mitofusin-1. A decrease in mitochondrial membrane potential at 1 and 1.5 µM indicates that Celastrol impaired mitochondrial function. Concurrently, an increase in mitochondrial reactive oxygen species and impaired upregulation of antioxidant enzymes were noted at 1.5 µM, indicating that Celastrol led to an imbalance in mitochondrial redox homeostasis. At both 1 and 1.5 µM, cell proliferation was inhibited, which may be related to the decreased expression levels of Cyclin-dependent kinase 1 and Cyclin B1. Celastrol extended the survival of GBM-afflicted mice.

CONCLUSION: Celastrol promotes mitochondrial fission in glioblastoma multiforme cells by reducing mitofusin-1 expression, accompanying mitochondrial dysfunction, lower mitochondrial membrane potential, heightened oxidative stress, and decreased Cyclin-dependent kinase 1 and Cyclin B1 levels. This indicates that Celastrol possesses potential for repurposing as an agent targeting mitochondrial dynamics in glioblastoma multiforme, warranting further investigation.

PMID:40050778 | DOI:10.1186/s12885-025-13733-9

Sci Rep. 2025 Mar 6;15(1):7840. doi: 10.1038/s41598-025-91757-8.

ABSTRACT

Drug repositioning is a transformative approach in drug discovery, offering a pathway to repurpose existing drugs for new therapeutic uses. In this study, we introduce the IDDNMTF model designed to predict drug repositioning opportunities with greater precision. The IDDNMTF model integrates multiple datasets, allowing for a more comprehensive analysis of drug-disease associations. We evaluated the IDDNMTF model using various combinations of datasets and found that its performance, as measured by AUC, AUPR, and F1 scores, improved with the inclusion of more data. This trend underscores the importance of data diversity in strengthening predictive capabilities. Comparatively, the IDDNMTF model demonstrated superior performance against the NMF model, solidifying its potential in drug repositioning. In summary, the IDDNMTF model offers a promising tool for identifying new therapeutic uses for existing drugs. Its predictive accuracy and interpretability are poised to accelerate the transition from bench to bedside, contributing to personalized medicine and the development of targeted treatments.

PMID:40050702 | DOI:10.1038/s41598-025-91757-8

Eur J Pharmacol. 2025 Mar 4:177461. doi: 10.1016/j.ejphar.2025.177461. Online ahead of print.

ABSTRACT

INTRODUCTION: & Aim: Novel treatments for idiopathic pulmonary fibrosis (IPF) are needed urgently. A better understanding of the molecular pathways activated by TGFβ1 in human lung tissue may facilitate the development of more effective anti-fibrotic medications. This study utilized proteomic analysis to test the hypothesis that TGFβ1 induces pro-fibrotic effects on human lung parenchyma proteome, and to evaluate the viability of this model for testing novel therapeutic targets.

METHODS: Non-fibrotic human lung parenchymal tissue from 11 patients was cultured for 7 days in serum-free (SF) media supplemented with TGFβ1 (10 ng/mL) or vehicle control, and the putative antifibrotic KCa3.1 ion channel blocker senicapoc or vehicle control. The tissue was homogenized, digested for bottom-up proteomics, and analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Principal component analysis, differential expression analysis, pathway analysis, and drug repurposing analysis were performed.

RESULTS: TGFβ1 stimulation for 7 days induced a strong fibrotic protein response relevant to IPF pathology. A total of 2,391 proteins were quantified, 306 upregulated and 285 downregulated (FDR-adjusted p-value<0.05). Of these, 118 were upregulated and 28 downregulated at log2(FC)>0.58. These changes were attenuated by senicapoc (100 nM). Drug repurposing analysis identified 265 drugs predicted to inhibit the effects of TGFβ1 in this model. These included clotrimazole, a KCa3.1 blocker, and nintedanib, a drug licenced for the treatment of IPF, providing validation of this approach.

CONCLUSION: A pro-fibrotic proteome is induced in human lung parenchyma exposed to TGFβ1, sensitive to pharmacological intervention. This approach has the potential to enhance therapeutic drug screening for IPF treatment.

PMID:40049575 | DOI:10.1016/j.ejphar.2025.177461

Adv Sci (Weinh). 2025 Mar 6:e2411325. doi: 10.1002/advs.202411325. Online ahead of print.

ABSTRACT

Drug repurposing identifies new therapeutic uses for the existing drugs originally developed for different indications, aiming at capitalizing on the established safety and efficacy profiles of known drugs. Thus, it is beneficial to bypass of early stages of drug development, and to reduction of the time and cost associated with bringing new therapies to market. Traditional experimental methods are often time-consuming and expensive, making artificial intelligence (AI) a promising alternative due to its lower cost, computational advantages, and ability to uncover hidden patterns. This review focuses on the availability of AI algorithms in drug development, and their positive and specific roles in revealing repurposing of the existing drugs, especially being integrated with virtual screening. It is shown that the existing AI algorithms excel at analyzing large-scale datasets, identifying the complicated patterns of drug responses from these datasets, and making predictions for potential drug repurposing. Building on these insights, challenges remain in developing efficient AI algorithms and future research, including integrating drug-related data across databases for better repurposing, enhancing AI computational efficiency, and advancing personalized medicine.

PMID:40047357 | DOI:10.1002/advs.202411325

Front Pharmacol. 2025 Feb 19;16:1519066. doi: 10.3389/fphar.2025.1519066. eCollection 2025.

ABSTRACT

BACKGROUND: Considering the role PARPs play in inflammation, we assessed the effect of PARP inhibition in an inflammatory skin condition, psoriasis, to explore novel avenues for the potential repurposing of PARP inhibitors that are currently used in tumour therapy.

METHODS: The imiquimod (IMQ)-induced model of psoriasis was applied in BALB/c mice. Mice received daily intraperitoneal injection of either one of four PARP inhibitors or their vehicle prior to treatment of the shaved back skin of mice with IMQ-containing cream or control cream for four days. The appearance of the skin of mice was scored daily according to the extent of erythema, induration and scaling. The most effective PARP inhibitor was selected for detailed studies on mouse skin and in a human keratinocyte cell line.

RESULTS: Of the PARP inhibitors, talazoparib and rucaparib improved the imiquimod-induced symptoms on mouse skin. Application of talazoparib in the psoriasis model resulted in maintained terminal differentiation and reduced proliferation of epidermal keratinocytes. Conversely, talazoparib also enhanced the production of pro-inflammatory chemokines in the skin of mice. These effects of talazoparib was associated with increased mitochondrial production of reactive oxygen species and a consequent activation of pro-apoptotic and pro-inflammatory pathways in keratinocytes.

CONCLUSION: PARP inhibition by talazoparib promotes terminal differentiation of epidermal keratinocytes that may be beneficial in psoriasis. Despite the fact that talazoparib exerted a pro-inflammatory effect in the skin, which is not unprecedented in anti-psoriatic therapy, these findings may advance the conduction of pre-clinical and clinical trials with PARP inhibitors in psoriasis management.

PMID:40046735 | PMC:PMC11879949 | DOI:10.3389/fphar.2025.1519066

Cancer Manag Res. 2025 Mar 1;17:429-440. doi: 10.2147/CMAR.S483151. eCollection 2025.

ABSTRACT

Pancreatic cancer (PC) remains one of the most challenging malignancies to treat. Current therapeutic options are unsatisfactory, and there is an urgent need for more effective and less toxic drugs to improve the dismal prognosis of PC. In recent years, drug repurposing (DR) has emerged as an attractive strategy to identify novel treatments for PC by leveraging existing drugs approved for other indications. Through the use of electronic medical records, Artificial Intelligence, study of metabolic pathways, signalling pathways, and many other approaches, it has become much easier in recent years to identify potential novel uses for old drugs. Although policy, funding and research attention in this area are steadily growing, major challenges to efficient and effective patient-centric DR in PC need to be addressed. These include but are not limited to regulatory, financial and funding barriers and the lack of coordination and collaboration among several sectors and stakeholders. To explore the opportunities and challenges associated with DR in PC, a one-day multi-stakeholder meeting was held on 14th of November 2024 in Brussels, Belgium as part of the REMEDi4ALL project. This meeting provided a platform for researchers, clinicians, industry representatives, funders, regulatory experts, and patient advocates to discuss and propose actions to optimize and accelerate DR in PC. Insights from this meeting support the potential of DR to enhance PC treatment options while highlighting the importance of systemic and supportive changes in the regulatory, policy and funding landscapes, interdisciplinary collaboration, data sharing, and patient involvement in driving therapeutic innovation. This summary highlights key outcomes and recommendations from the meeting in informing future efforts to advance DR initiatives in the context of PC.

PMID:40046652 | PMC:PMC11881603 | DOI:10.2147/CMAR.S483151

J Cachexia Sarcopenia Muscle. 2025 Apr;16(2):e13661. doi: 10.1002/jcsm.13661.

ABSTRACT

BACKGROUND: Sarcopenia presents a pressing public health concern due to its association with age-related muscle mass decline, strength loss and reduced physical performance, particularly in the growing older population. Given the absence of approved pharmacological therapies for sarcopenia, the need to discover effective pharmacological interventions has become critical.

METHODS: To address this challenge and discover new therapies, we developed a novel Multi-Task Attention-aware method for Multi-Omics data (MTA-MO) to extract complex biological insights from various biomedical data sources, including transcriptome, methylome and genome data to identify drug targets and discover new therapies. Additionally, MTA-MO integrates human protein-protein interaction (PPI) networks and drug-target networks to improve target identification. The novel method is applied to a multi-omics dataset that included 1055 participants aged 20-50 (mean (± SD) age 36.88 (± 8.64)), comprising 37.82% African-American and 62.18% Caucasian/White individuals. Physical activity levels were self-reported and categorized into three groups: ≥ 3 times/week, < 3 times/week and no regular exercise. Mean (± SD) measures for grip strength, appendicular lean mass (ALM), exercise frequency and smoking status (no/yes, n (%)) were 38.72 (± 8.93) kg, 28.65 (± 4.63) kg, 4.31 (± 1.79) and 30.81%/69.19%, respectively. Significant differences (p < 0.05) were found between groups in age, ALM, smoking, and consumption of milk, alcohol, beer and wine.

RESULTS: Using the MTA-MO method, we identified 639 gene targets, and by analysing PPIs and querying public databases, we narrowed this list down to seven potential hub genes associated with sarcopenia (ESR1, ATM, CDC42, EP300, PIK3CA, EGF and PTK2B). These findings were further validated through diverse levels of pathobiological evidence associated with sarcopenia. Gene Ontology and KEGG pathways analysis highlighted five key functions and signalling pathways relevant to skeletal muscle. The interaction network analysis identified three transcriptional factors (GATA2, JUN and FOXC1) as the key transcriptional regulators of the seven potential genes. In silico analysis of 1940 drug candidates identified canagliflozin as a promising candidate for repurposing in sarcopenia, demonstrating the strongest binding affinity to the PTK2B protein (inhibition constant 6.97 μM). This binding is stabilized by hydrophobic bonds, Van der Waals forces, pi-alkyl interactions and pi-anion interactions around PTK2B's active residues, suggesting its potential as a therapeutic option.

CONCLUSIONS: Our novel approach effectively integrates multi-omics data to identify potential treatments for sarcopenia. The findings suggest that canagliflozin could be a promising therapeutic candidate for sarcopenia.

PMID:40045692 | DOI:10.1002/jcsm.13661

Parasite. 2025;32:18. doi: 10.1051/parasite/2025009. Epub 2025 Mar 5.

ABSTRACT

Leishmaniases are vector-borne parasitic diseases that pose a threat to over 1 billion people worldwide. The parasites target cells of the reticulohistiocytic system, such as macrophages, where they replicate. The disease manifests in various forms, ranging from localized cutaneous leishmaniasis to life-threatening visceral forms, which are fatal in 95% of cases without treatment. Current treatments rely on the invasive administration of toxic and expensive drugs that are increasingly encountering resistance. Therefore, finding alternative treatments for this disease is imperative. This literature review focuses on recent advancements in alternative treatments and aims to present the various strategies designed to address current limitations, including cost, toxicity, off-target effects, administration routes, and the emergence of drug resistance. Starting with an overview of the existing approved treatments and their specific limitations, we categorize treatment development strategies into five key sections: (i) combination therapies using existing approved treatments to enhance efficacy and reduce resistance; (ii) nanoparticle formulations, which enable targeted delivery to infected organs and improved therapeutic efficiency; (iii) drug repositioning, a strategy that has already contributed to the approval of over half of current therapeutic compounds; (iv) immunomodulation, used in conjunction with standard chemotherapies to enhance treatment efficacy and lower relapse rates; and (v) ethnobotanicals, which have demonstrated promising in vitro results by combining low toxicity, immunomodulatory properties, and potent anti-parasitic effects. In summary, this review outlines current strategies in treatment development, emphasizing their advantages over conventional therapies while acknowledging their limitations.

PMID:40043198 | DOI:10.1051/parasite/2025009

Toxicol Res (Camb). 2025 Feb 27;14(1):tfaf025. doi: 10.1093/toxres/tfaf025. eCollection 2025 Feb.

ABSTRACT

Melasma is a chronic condition that leads to the buildup of melanin pigment in the epidermis and dermis due to active melanocytes. Even though it is considered a non-life-threatening condition, pigment disorders have a negative impact on quality of life. Since melasma treatment is not sufficient and complicated, new treatment options are sought. Research on metformin and ascorbic acid suggested that they might be used against melasma in the scope of "drug repositioning."The MNT-1 human melanoma cell line was used to assess the effects of metformin, ascorbic acid, and metformin+ascorbic acid combination on cytotoxicity and oxidative stress. Melanin, cAMP, L-3,4-dihydroxyphenylalanine (L-DOPA) and tyrosinase levels were determined by commercial ELISA kits and tyrosinase gene expression was analyzed with RT-qPCR. Cytopathological evaluations were performed by phase contrast microscopy. Tyrosinase expression was determined by immunofluorescence (IF) staining of MNT-1 cells. The online service TargetNet was used for biological target screening. The parameters were not significantly altered by ascorbic acid applied at non-cytotoxic concentrations. On the contrary, metformin dramatically raised tyrosinase and intracellular ROS levels. Moreover, intracellular ROS levels and tyrosinase levels were found to be considerably elevated with the combined treatment. Also, potential metformin and ascorbic acid interactions were determined. According to the results, it can be said that these parameters were not significantly altered by ascorbic acid. On the contrary, metformin dramatically raised tyrosinase and intracellular oxidative stress levels. Moreover, intracellular oxidative stress and tyrosinase levels were elevated with the combined treatment. In conclusion, individual treatments of ascorbic acid or metformin may only provide a limited effect when treating melasma and extensive in vitro and in vivo research are required.

PMID:40040652 | PMC:PMC11878769 | DOI:10.1093/toxres/tfaf025

Annu Int Conf IEEE Eng Med Biol Soc. 2024 Jul;2024:1-7. doi: 10.1109/EMBC53108.2024.10782657.

ABSTRACT

Drug-target interaction (DTI) prediction speeds up drug repurposing, accelerates drug screening, and reduces drug design timeframe. Previous DTI prediction frameworks lack consideration for the multimodal nature of DTI, advanced feature representation techniques, and generalizability on unseen drugs and proteins. Therefore, we propose a novel framework that combines a multimodal graph neural network with direct, molecular-level structural learning via model ensembling. We use a multimodal biomedical that contains drugs, proteins, diseases, and pathways, all of which have meaningful feature embeddings generated via language models or knowledge graphs. We also employ a structural learning module that exploits molecular-level information and runs independently from the graph. Lastly, the graph and structural modules are combined, forming the optimal prediction. Our proposed framework outperformed multiple benchmark DTI frameworks on real-world datasets. After testing on an independent dataset, we conclude our framework is generalizable to unseen drugs and proteins. Our model can be easily extended to other biomedical link prediction problems, such as drug-drug interaction.

PMID:40040060 | DOI:10.1109/EMBC53108.2024.10782657

Cell Mol Biol Lett. 2025 Mar 5;30(1):27. doi: 10.1186/s11658-025-00710-0.

ABSTRACT

The "War on Cancer" began with the National Cancer Act of 1971 and despite more than 50 years of effort and numerous successes, there still remains much more work to be done. The major challenge remains the complexity and intrinsic polygenicity of neoplastic diseases. Furthermore, the safety of the antitumor therapies still remains a concern given their often off-target effects. Although the amount of money invested in research and development required to introduce a novel FDA-approved drug has continuously increased, the likelihood for a new cancer drug's approval remains limited. One interesting alternative approach, however, is the idea of repurposing of old drugs, which is both faster and less costly than developing new drugs. Repurposed drugs have the potential to address the shortage of new drugs with the added benefit that the safety concerns are already established. That being said, their interactions with other new drugs in combination therapies, however, should be tested. In this review, we discuss the history of repurposed drugs, some successes and failures, as well as the multiple challenges and obstacles that need to be addressed in order to enhance repurposed drugs' potential for new cancer therapies.

PMID:40038587 | DOI:10.1186/s11658-025-00710-0

Nat Commun. 2025 Mar 4;16(1):2159. doi: 10.1038/s41467-025-57476-4.

ABSTRACT

The targeting of cancer stem cells (CSCs) has proven to be an effective approach for limiting tumor progression, thus necessitating the identification of new drugs with anti-CSC activity. Through a high-throughput drug repositioning screen, we identify the antibiotic Nifuroxazide (NIF) as a potent anti-CSC compound. Utilizing a click chemistry strategy, we demonstrate that NIF is a prodrug that is specifically bioactivated in breast CSCs. Mechanistically, NIF-induced CSC death is a result of a synergistic action that combines the generation of DNA interstrand crosslinks with the inhibition of the Fanconi anemia (FA) pathway activity. NIF treatment mimics FA-deficiency through the inhibition of STAT3, which we identify as a non-canonical transcription factor of FA-related genes. NIF induces a chemical HRDness (Homologous Recombination Deficiency) in CSCs that (re)sensitizes breast cancers with innate or acquired resistance to PARP inhibitor (PARPi) in patient-derived xenograft models. Our results suggest that NIF may be useful in combination with PARPi for the treatment of breast tumors, regardless of their HRD status.

PMID:40038300 | DOI:10.1038/s41467-025-57476-4

IEEE J Biomed Health Inform. 2025 Feb 21;PP. doi: 10.1109/JBHI.2025.3542784. Online ahead of print.

ABSTRACT

The research on identifying drug-disease associations (DDAs) is widely used in scenarios such as drug development, clinical decision-making, and drug repurposing, holding significant biological and medical significance. Existing methods for drug-disease association prediction have achieved decent performance, they primarily rely on simplistic drug-disease association graphs or similarity graphs. These methods often struggle to capture the high-order correlations of complex multimodal data, limiting their ability to handle the complexity of data associations effectively. In addition, real drug-disease associations are highly sparse, posing a significant challenge to prediction accuracy. To tackle these issues, we propose a general hypergraph neural network framework for drug-disease association prediction based on hierarchical contrastive learning and cross-attention learning. It leverages hypergraph neural networks to learn representations of drugs and diseases carrying high-order correlations and strengthens representation quality using interactive attention learning and hierarchical contrastive learning. Meanwhile, the -weighted loss function is utilized to adapt to the high sparsity property of real drug-disease associations during model training and improve prediction performance. Extensive experiments demonstrate that DD-HGNN surpasses other state-of-the-art methods in predicting drug-disease associations and further validation through case studies on Leukemia and Colorectal Neoplasms underscores its reliability.

PMID:40036538 | DOI:10.1109/JBHI.2025.3542784

iScience. 2025 Jan 31;28(3):111931. doi: 10.1016/j.isci.2025.111931. eCollection 2025 Mar 21.

ABSTRACT

FoxP3+ regulatory T cells (Tregs) are responsible for immune homeostasis by suppressing excessive anti-self-immunity. Tregs facilitate tumor growth by inhibiting anti-tumor immunity. Here, we explored the targeting of FoxP3 as a basis for new immunotherapies. In a high-throughput phenotypic screening of a drug repurposing library using human primary T cells, we identified quinacrine as a FoxP3 downregulator. In silico searches based on the structure of quinacrine, testing of sub-libraries of analogs in vitro, and validation identified a subset of 9-amino-acridines that selectively abrogated Treg suppressive functions. Mechanistically, these acridines interfered with the DNA-binding activity of FoxP3 and inhibited FoxP3-regulated downstream gene regulation. Release from Treg suppression by 9-amino-acridines increased anti-tumor immune responses both in cancer patient samples and in mice in a syngeneic tumor model. Our study highlights the feasibility of screening for small molecular inhibitors of FoxP3 as an approach to pursuing Treg-based immunotherapy.

PMID:40034859 | PMC:PMC11872463 | DOI:10.1016/j.isci.2025.111931

Front Pharmacol. 2025 Feb 17;16:1504618. doi: 10.3389/fphar.2025.1504618. eCollection 2025.

ABSTRACT

Achyranthes japonica (Miq.) Nakai (AJN) and Melandrium firmum (Siebold and Zucc.) Rohrb. (MFR) are medicinal plants recognized for their bioactive phytochemicals, including ecdysteroids, anthraquinones, and flavonoids. This study investigates the anticancer properties of key constituents of these plants, focusing on the BK002 formulation, a novel combination of AJN and MFR. Specifically, the research employs advanced molecular docking and in silico analyses to assess the interactions of bioactive compounds ecdysterone, inokosterone, and 20-hydroxyecdysone (20-HE) with key prostate cancer-related network proteins, including 5α-reductase, CYP17, DNMT1, Dicer, PD-1, and PD-L1. Molecular docking techniques were applied to evaluate the binding affinities contributions of the bioactive compounds in BK002 against prostate cancer-hub network targets. The primary focus was on enzymes like 5α-reductase and CYP17, which are central to androgen biosynthesis, as well as on cancer-related proteins such as DNA methyltransferase 1 (DNMT1), Dicer, programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1). Based on data from prostate cancer patients, key target networks were identified, followed by in silico analysis of the primary bioactive components of BK002.In silico assessments were conducted to evaluate the safety profiles of these compounds, providing insights into their therapeutic potential. The docking studies revealed that ecdysterone, inokosterone, and 20-hydroxyecdysonec demonstrated strong binding affinities to the critical prostate cancer-related enzymes 5α-reductase and CYP17, contributing to a potential reduction in androgenic activity. These compounds also exhibited significant inhibitory interactions with DNMT1, Dicer, PD-1, and PD-L1, suggesting a capacity to interfere with key oncogenic and immune evasion pathways. Ecdysterone, inokosterone, and 20-hydroxyecdysone have demonstrated the ability to target key oncogenic pathways, and their favorable binding affinity profiles further underscore their potential as novel therapeutic agents for prostate cancer. These findings provide a strong rationale for further preclinical and clinical investigations, supporting the integration of BK002 into therapeutic regimens aimed at modulating tumor progression and immune responses.

PMID:40034825 | PMC:PMC11872924 | DOI:10.3389/fphar.2025.1504618