Search Results (110)

Background/Objectives: Type 2 diabetes mellitus (DM) commonly coexists with heart failure (HF) and is associated with increased cardiovascular (CV) morbidity and mortality. Although dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used for glycemic control, their CV safety in patients with established HF, particularly across HF phenotypes, remains uncertain. To evaluate the association between DPP-4 inhibitor use and 6-month CV mortality in patients with DM and HF, and to assess whether this association differs across HF phenotypes: HF with preserved ejection fraction (HFpEF), HF with mildly reduced ejection fraction (HFmrEF), HF with reduced ejection fraction (HFrEF). Methods: We conducted a retrospective cohort study at King Abdulaziz Medical City from January 2017 to December 2024 that included adults with DM and echocardiographically confirmed HF. Patients receiving DPP-4 inhibitors were compared with non-users. The primary outcome was 6-month CV mortality. Propensity score overlap weighting targeting the average treatment effect in the overlap population was applied to balance baseline characteristics. Weighted logistic regression with interaction terms was used to assess effect modification by HF phenotype. Results: Among 3435 patients (median age 69 years; 51.3% female), 1921 (55.9%) received a DPP-4 inhibitor, predominantly sitagliptin. In unadjusted analyses, CV mortality was numerically lower among DPP-4 inhibitor users across HF phenotypes. However, after overlap weighting, CV mortality was similar between users and non-users within HFpEF (7.1% vs. 8.0%; OR 0.88, 95% CI 0.51–1.52; p = 0.646), HFmrEF (2.6% vs. 5.0%; OR 0.50, 95% CI 0.09–2.86; p = 0.436), and HFrEF (6.4% vs. 6.4%; OR 1.00, 95% CI 0.48–2.07; p = 0.992). No significant interaction was observed between DPP-4 inhibitor use and HF phenotype (interaction p > 0.05). Conclusions: In this large real-world cohort of patients with DM and established HF, DPP-4 inhibitor use was not associated with increased or reduced 6-month CV mortality after robust adjustment. The neutral association was consistent across HF phenotypes, supporting the CV safety of DPP-4 inhibitors, predominantly sitagliptin, in contemporary HF management. Full article

Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used to treat type 2 diabetes. However, several studies have demonstrated its anti-inflammatory and immunomodulatory properties. The aim of this study was to investigate the effect of sitagliptin on the functional and phenotypic properties of human neutrophils under normal (NG, 5.5 mM)- and high (HG, 22 mM)-glucose conditions in vitro. Neutrophils were pretreated with varying concentrations of sitagliptin and stimulated with phorbol-12-myristate-13-acetate (PMA), N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), calcium ionophore (CaI), or opsonized zymosan (OpZym). Survival, phenotypic, and functional characteristics were then assessed. Our results showed that sitagliptin was non-cytotoxic to neutrophils even at very high concentrations. It decreased the production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), generally following a stimulus- and concentration-dependent pattern. The effect was more pronounced under HG conditions. Furthermore, sitagliptin showed a significant ROS-scavenging effect in a cell-free system. It also rapidly altered the expression of surface markers in both resting and fMLP-stimulated neutrophils, typically upregulating CD10, CD16, CD62L, CD63, CD88, CD89, and PD-L1, and downregulating CD11b/CD18, CD66b, and CD182, a phenotype consistent with a dampened, less-primed activation state of these cells. In conclusion, sitagliptin exhibited marked antioxidative/ROS-scavenging activity in neutrophil cultures and induced a coordinated shift in neutrophil phenotype, accompanied by suppression of NETosis under both NG and HG conditions. Collectively, these data support the view that neutrophils may constitute an additional cellular target contributing to sitagliptin’s anti-inflammatory and immunomodulatory profile. Full article

The present work set out to examine the antidiabetic capacity of Abelmoschus esculentus (okra) fruit extract through a combined experimental and computational framework. Enzyme inhibition assays were carried out against four metabolic targets, and IC₅₀ values stood at 7.66 ± 0.31 mg/mL for alpha-glucosidase, 5.21 ± 0.18 mg/mL for alpha-amylase, 2.11 ± 0.15 microg/mL for DPP-4, and 9.17 ± 0.54 mg/mL for pancreatic lipase. The extract showed moderate-to-weak activity relative to standard inhibitors acarbose, sitagliptin, and orlistat. Sixteen drug-like phytochemicals obtained from the IMPPAT 2.0 database were docked against the crystal structures of all four tested enzymes (PDB: 8CB1, 5E0F, 2ONC, 1LPB). Alpha-Carotene, Vitamin E, and Spiraeoside emerged as the top-ranked compounds across all targets, with alpha-Carotene recording the strongest binding affinity of −11.1 kcal/mol against pancreatic lipase, which was 4.2 kcal/mol more negative than the positive control orlistat (−6.9 kcal/mol). PLIP-based interaction profiling mapped out hydrogen bonds, hydrophobic contacts, pi-stacking, and salt bridges at the atomic level. Absorption, distribution, metabolism, and excretion (ADME) and toxicity screening of alpha-Carotene returned a favourable pharmacokinetic profile with predicted LD₅₀ of 1510 mg/kg (Class 4) and inactivity across most toxicity endpoints. A 100 ns molecular dynamics simulation of the pancreatic lipase-alpha–Carotene complex, alongside the orlistat control, showed stable root mean square deviation (RMSD) (0.15–0.22 nm), a consistent Rg (~1.97 nm), and sustained hydrogen bonding throughout the trajectory. Free-energy landscape analysis revealed a well-defined single energy basin for alpha-Carotene, suggesting a thermodynamically stable binding conformation. These findings lay the molecular basis for using okra phytochemicals as adjunctive agents in diabetes management, though in vivo validation remains necessary. Full article

Background/Objectives: For patients diagnosed with chronic kidney disease (CKD), it is important to follow guidelines addressing dose-adjustments for renally eliminated drugs to avoid complications related to toxicity and subtherapeutic effects. In Saudi Arabia, limited data are available regarding appropriate medication doses for CKD. In this study, we investigated the prevalence of inappropriately administered drugs in patients with CKD and examined factors associated with unadjusted renal dosing. Methods: A retrospective, cross-sectional, observational analysis (2023–2025) was conducted via a systematic electronic medical record review of hospitalized patients diagnosed with CKD and cardiovascular diseases (CVDs) in the Al-Baha region, Saudi Arabia. Medications were selected and evaluated for appropriate dosing based on creatinine clearance (CrCl). Medications were categorized as appropriately adjusted, inappropriately adjusted, unadjusted, or contraindicated. Results: A total of 440 patients (787 prescriptions) were included. At the patient level, 85% had at least one appropriately adjusted medication, 13% had at least one inappropriately adjusted medication, 30% had at least one medication that was not adjusted despite indication, 34% had at least one medication requiring no adjustment, and 17% had at least one contraindicated medication (categories are not mutually exclusive). At the prescription level, which was the primary analytic unit (N = 787), 48% of prescriptions were appropriately adjusted, 7% were inappropriately adjusted, 17% were not adjusted despite indication, 19% required no adjustment, and 10% were contraindicated. Antibiotics accounted for the largest share of inappropriate adjustments, representing 77% (43/56) of all inappropriate dose-adjustment events. In exploratory bivariate analyses, age was not statistically significantly associated with dosing outcomes (Holm-adjusted p = 0.145). Polypharmacy was highly prevalent (91% of patients) but was not significantly associated with any dosing outcome in these exploratory analyses, likely due to limited statistical power. Conclusions: Our results showed that several regularly prescribed drugs, including metformin, sitagliptin, ceftazidime, ciprofloxacin, and spironolactone, were inappropriately prescribed to patients with CKD. These dosing errors can be avoided by increasing clinicians’ and pharmacists’ awareness of appropriate dosage modifications essential for patients with CKD. Full article

An excessive activation of the tryptophan–kynurenine (TRP-KYN) pathway, frequently observed in metabolic and inflammatory disorders, leads to disturbances in the balance between neurotoxic and neuroprotective metabolites. These alterations may contribute to neuronal dysfunction and cognitive impairment, highlighting the importance of modulating this pathway in the context of neuroprotection. Metformin, apart from the AMPK activation and its broad anti-inflammatory actions, has been indicated as a drug capable of influencing the synthesis of TRP metabolites, including the neuroprotective kynurenic acid (KYNA), whereas the effects of sitagliptin in this regard are not known. Here, the effects of sub-chronic metformin or sitagliptin treatment on the brain levels of kynurenines and on functional alterations within the TRP-KYN pathway were evaluated in vivo, in adult non-diabetic Wistar male rats. A 5-day treatment with metformin decreased cortical TRP and KYNA, hippocampal KYN, and cerebellar levels of all studied kynurenines, whereas in the striatum, KYNA level increased. In contrast, sitagliptin did not alter the formation of kynurenines in the examined structures. However, both of the tested drugs had a significant impact on TRP/L-KYN or L-KYN/KYNA ratios in different parts of the brain. These findings indicate a prominent region-specific effect of metformin on brain kynurenines. In conclusion, commonly used antidiabetic agents differ in their impact on central TRP metabolism, which may have significant implications for understanding their potential neuroprotective effects and role in cognitive impairment. Full article

Background: In internal medicine, the management of type 2 diabetes mellitus (T2DM) is challenged by multimorbidity and polypharmacy. The fixed-dose combination of sitagliptin and extended-release metformin (SITA/MET ER) is a valuable option for frail and comorbid patients. Methods: This multicenter, retrospective, observational study involved five Italian Internal Medicine units. Consecutive patients with T2DM who initiated SITA/MET ER were included. Demographic, clinical, and laboratory data were collected at baseline (T0) and at follow-up (T1, 3–4 months). The primary endpoint was change in HbA1c; secondary endpoints included fasting plasma glucose (FPG), treatment adherence, adverse events, and modifications in concomitant antidiabetic therapies. Results: A total of 292 patients (mean age 70.8 ± 10.6 years; 43% female) were analyzed. At baseline, mean HbA1c was 7.4 ± 1.0% and FPG 150.2 ± 42.5 mg/dL, with significant reductions observed at follow-up (HbA1c 7.0 ± 0.8%, FPG 136.8 ± 29.6 mg/dL; both p < 0.05). SITA/MET ER was predominantly prescribed to patients with a complex clinical profile, as reflected by the high prevalence of microvascular (37%) and macrovascular (42%) complications. The use of sulfonylureas decreased from 11% to 3% (p < 0.001), while SGLT2 inhibitor and insulin use remained stable. Treatment adherence to SITA/MET ER was excellent, with full compliance reported and no adverse events recorded. Conclusions: In this real-world internal medicine study, SITA/MET ER improved glycemic control and was well tolerated among patients with complex clinical profiles. These findings support the role of SITA/MET ER as a flexible and practical therapeutic choice in this setting. Full article

Cardiovascular diseases (CVDs) represent one of the leading causes of morbidity and mortality in patients with diabetes. However, a correct and effective glycaemic control obtained by pharmacologic interventions, such as the use the novel glucose-lowering agents, demonstrated efficacy in reducing the risk of both cardiovascular events and mortality. The latest classes of glucose-lowering drugs introduced in the clinical practice are DPP4 inhibitors (sitagliptin, saxagliptin, vildagliptin, linagliptin, and alogliptin), GLP-1 receptor agonists (semaglutide, liraglutide, albiglutide, dulaglutide, exenatide, and lixenatide), and SGLT-2 inhibitors (empaglifozin, canaglifozin, and dapaglifozin). Multiple lines of evidence show that all these new drugs associated with the treatment of diabetic disease have the same effectiveness as the traditional antidiabetic drugs, and excellent cardiovascular safety, highlighting their potential in significantly reducing major cardiovascular events and mortality. The aim of our review is to summarise the clinical efficacy of these recently introduced drugs to optimise treatment strategies, especially in the early phase of diabetic disease. Full article

Background/Objectives: Cervical cancer remains a major global health challenge, and treatment resistance limits the long-term success of chemotherapy. Drug repurposing strategies offer new opportunities for improving therapeutic outcomes by combining existing agents with established chemotherapeutics. Sitagliptin, a DPP-4 inhibitor commonly used in type 2 diabetes, has recently gained attention for its potential anticancer effects. This study aimed to investigate the cytotoxic, apoptotic, and anti-metastatic effects of sitagliptin and doxorubicin, individually and in combination, on human cervical cancer cells (HeLa), and to determine whether their combined use exerts a synergistic anticancer effect. Methods: HeLa cells were treated for 48 h with increasing concentrations of sitagliptin, doxorubicin, or their combination. Cell viability was assessed using the MTT assay. Apoptosis was evaluated by Annexin V-FITC/PI staining and caspase-8/9 activity assays. Synergy was quantified using the Chou–Talalay method, and Combination Index (CI) values were used to determine synergistic interactions. Intracellular ROS levels were measured using the DCFDA assay. Migration and invasion capacities were analyzed using wound healing and Transwell assays. MMP-1, MMP-2, TIMP-1, and TIMP-2 levels were quantified via ELISA with normalization to viable cell counts. Gene expression levels of PI3K/Akt and MAPK/ERK pathway components were measured by qRT-PCR. Bioinformatic analyses (STRING, GeneMANIA, GO, KEGG) were performed to identify common molecular targets and enriched pathways affected by both agents. Results: The combination of sitagliptin and doxorubicin significantly reduced cell viability and demonstrated a synergistic interaction (CI < 1). Combined treatment induced a marked increase in ROS production and significantly elevated apoptosis rates compared to monotherapies. Caspase-8 and caspase-9 activities were also higher in the combination group. Migration and invasion assays revealed substantial suppression of cell motility and invasive capacity. After normalization to viable cell numbers, MMP and TIMP reductions remained significant, confirming true biological inhibition rather than cell-death–related artifacts. qRT-PCR analyses showed downregulation of Akt and ERK expression, indicating suppression of key survival and proliferation pathways. Bioinformatic analyses supported these findings by highlighting enrichment in apoptotic, oxidative stress, and metastasis-related pathways. Conclusions: Sitagliptin enhances the anticancer efficacy of doxorubicin by amplifying ROS-mediated apoptosis, inhibiting migration and invasion, and modulating PI3K/Akt and MAPK/ERK signaling in cervical cancer cells. The combination exhibits a clear synergistic effect and demonstrates strong potential as a supportive therapeutic strategy. These findings warrant further in vivo and clinical-level investigations to evaluate the translational applicability of sitagliptin in cervical cancer therapy. Full article

Glaucoma is a neurodegenerative disease characterized by progressive degeneration of optic nerve axons and loss of retinal ganglion cells (RGCs). Although elevated intraocular pressure (IOP) is a major risk factor, many patients develop glaucoma with normal IOP, highlighting the need for neuroprotective therapies. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, has shown beneficial effects in diabetes-induced retinal neurodegeneration. This study aimed to evaluate whether sitagliptin eye drops, previously effective in diabetes-induced retinal neurodegeneration, could prevent corticosteroid-induced glaucoma. Glaucoma was induced in mice by periocular injection of dexamethasone (DEX) once weekly for five weeks. Sitagliptin or vehicle eye drops were administered from day 14 to 35. Untreated mice served as controls. DEX treatment caused significant loss of RGC bodies and optic nerve axons compared to controls, which was prevented by sitagliptin eye drops (p < 0.001), without affecting IOP. Sitagliptin also inhibited DEX-induced activation of macroglia and microglia and prevented oligodendrocyte loss. Furthermore, it suppressed overexpression of galectin-3 and gamma-synuclein in the optic nerve head (ONH) (p < 0.001), key mediators of inflammation and apoptosis. Sitagliptin eye drops exert a potent neuroprotective effect against corticosteroid-induced glaucoma, supporting their potential as a novel therapeutic strategy for glaucoma. Full article

This study investigated the potential of scale-up mango leaf extract (MLE) as a treatment for diabetes, a global public health concern. MLE was prepared by boiling in water, yielding 12.07% (w/w), with a bioactive mangiferin content of 165.67 ± 10.88 μg/g in the crude powder. Mechanistically, MLE demonstrated a hypoglycemic effect by stimulating glucagon-like peptide-1 (GLP-1) secretion in NCI-H716 L-cells. This occurred through activation of the MAPK signaling pathway, evidenced by increased p-ERK1/2, p-p38, and p-c-Jun expression, and the Wnt signaling pathway, shown by increased β-catenin and decreased GSK-3β and Axin1 expression, consistent with molecular docking. In a type 2 diabetic rat model, MLE administration (40 mg/kg) significantly reduced metabolic parameters, including fasting blood glucose (FBG), body weight, cholesterol (CHOL), triglycerides (TGs), and HbA1c. Notably, MLE lowered serum insulin and the HOMA-IR index, and reduced serum dipeptidyl peptidase-IV (DPP-IV) levels, resulting in increased serum GLP-1, comparable to the drug sitagliptin. These findings suggest that MLE has great potential to lower blood glucose by inducing GLP-1 secretion via MAPKs and Wnt signaling pathways, positioning it as a promising candidate for alternative diabetes treatment or development as a dietary supplement. Full article

Background: Radiation-induced tissue degeneration is the most important side effect of radiotherapy. Sitagliptin with its anti-inflammatory and antioxidant capacity was tested in alleviating the radiation-induced cellular degeneration in kidney and testis tissues. Methods: Wistar albino rats were divided into four groups as control, radiation (RT), radiation + sitagliptin (RT + SGT), and sitagliptin + radiation (SGT + RT). The RT group received 8 Gy radiation. Sitagliptin was applied per os at a 10 mg/kg dose for 14 days to the SGT groups either after or before radiation. Results: Radiation induced marked oxidative stress in kidney and testis tissues, whereas sitagliptin partially restored several antioxidant parameters in the kidney and reduced MDA levels in the testis. Histologically, radiation caused degenerative changes in the renal tubules and glomerulus and the testicular seminiferous tubules, while sitagliptin treatment attenuated these changes in both organs. Caspase-3 expression increased significantly after radiation treatment in the kidney without substantial improvement by sitagliptin; however, VEGF expression, which was markedly reduced by radiation in both tissues, was restored in sitagliptin-treated groups. FGF expression suppressed in all irradiated groups as compared to the control with no significant differences among them. Conclusions: Overall, the results indicated that sitagliptin can be used to attenuate the degenerative effects induced by radiation. Sitagliptin use after radiation as compared to the before use showed significantly better results especially in the kidney tissue. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance, impaired insulin secretion, and chronic hyperglycemia. Recent studies have identified microRNAs (miRNAs), a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level, as modulators of pathways involved in T2DM pathophysiology. Dysregulated miRNA expression has been detected in various samples collected from patients with T2DM, implicating these molecules in disease onset and progression. Methods: We systematically searched PubMed, Scopus, and Web of Science for studies published from the earliest available records to 18 August 2025 using the following Boolean search terms: “miRNA AND gliclazide”, “miRNA AND glibenclamide”, “miRNA AND gliquidone”, “miRNA AND glimepiride”, “mirRNA AND metformin”, “miRNA AND pioglitazone”, “miRNA AND rosiglitazone”, “miRNA AND sitagliptin”, “miRNA AND vildagliptin”, “miRNA AND alogliptin”, “miRNA and saxagliptin”, “miRNA AND linagliptin”, “miRNA AND liraglutide”, “miRNA and dulaglutide”, “miRNA AND semaglutide”, “miRNA AND tirzepatide”, “miRNA AND lixisenatide”, “miRNA AND empagliflozin”, “miRNA AND dapagliflozin”, miRNA AND insulin glargine”, “miRNA AND insulin detemir”, “miRNA AND insulin degludec”, “miRNA AND insulin aspart”, “miRNA AND insulin glulisine”, and “miRNA AND insulin lispro”. Additionally, gray literature was searched in ClinicalTrials.gov, the EU Clinical Trials Register (EudraCT), and the ISRCTN Registry to identify unpublished studies. Studies were eligible for inclusion if they were clinical interventional studies assessing the impact of currently available antidiabetic treatments on miRNA expression. Only articles published in English were considered. The risk of bias was evaluated using the RoB2 (Risk of Bias 2) and ROBINS-I (Risk Of Bias In Non-randomized Studies—of Interventions) tools. Study characteristics and major findings were tabulated. Results: A total of 1263 manuscripts was identified initially. After removing duplicates, 726 articles remained for further screening. Ultimately, 17 manuscripts reporting interventional clinical trials on the effects of antidiabetic treatment on miRNA were included, encompassing a total of 1093 patients. Key findings included treatment-associated changes in miRNA expression and their potential utility for the prediction of clinical outcomes. Conclusions: Current evidence supports the hypothesis that antidiabetic treatments modulate miRNA expression, with some findings showing predictive value for metabolic outcomes. However, the available data remain limited and of low grade of certainty, and further large-scale clinical studies are needed to provide deeper insights into these associations. Full article

The role of insulin-like growth factor-binding proteins (IGFBPs) in the regulation of carbohydrate metabolism and the development of complications is well established; however, the impact of the glucagon-like peptide-1 receptor agonist semaglutide on IGFBPs has not been previously investigated. We aimed to examine the effects of semaglutide and dipeptidyl peptidase-4 inhibitor sitagliptin therapy on serum levels of IGFBP-1, IGFBP-3, and IGFBP-rp1, and to analyze their associations with anthropometric variables and markers of carbohydrate and lipid metabolism. In this prospective study, we enrolled 34 patients with type 2 diabetes mellitus (T2DM) on metformin monotherapy and 31 age-, sex- and BMI-matched controls. Among the patients, 18 received semaglutide, and 16 were treated with sitagliptin. Anthropometric and laboratory assessments were performed at baseline, 26 and 52 weeks. IGFBP levels were measured using ELISA. Both semaglutide and sitagliptin treatment significantly increased IGFBP-1 levels. IGFBP-3 levels were significantly decreased following sitagliptin therapy. No significant change in IGFBP-rp1 levels was observed with either treatment. Based on multiple regression analysis, the best predictors of IGFBP-1 were insulin and hsCRP, while the best predictor of IGFBP-3 was LDL-C level. Our findings suggest that semaglutide and sitagliptin may exert favorable effects on the GH/IGF-1 axis, potentially contributing to their beneficial metabolic outcomes in patients with T2DM. Full article

Background/Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that regulate blood glucose by preventing the degradation of active incretin hormones. Although clinically effective, this drug class is associated with adverse effects, creating the need for new molecular scaffolds with improved safety and efficacy. Methods: We evaluated the antihyperglycemic activity of β-aminohydrazine and β-amino-N-acylhydrazone derivatives (LASSBio-2123, 2125, 2129, and 2130) using a combined in vivo and in silico approach. Male C57BL/6 mice underwent glucose tolerance tests (GTT) and dexamethasone-induced insulin resistance protocols. Hepatic and skeletal muscle glycogen levels, as well as GLUT4 mRNA expression, were quantified. In silico studies included ADMET predictions and molecular docking analyses against aldose reductase and glucokinase enzymes. MTT was performed on the pancreatic cell line MIN6 (Mus musculus). Results: Among the compounds tested, LASSBio-2129 demonstrated the most promising profile, with favorable ADMET parameters, metabolic stability, and high docking affinity for aldose reductase and glucokinase. In vivo, LASSBio-2129 (10 mg/kg, i.p.) reduced blood glucose, increased hepatic and muscle glycogen storage, and upregulated GLUT4 mRNA expression in skeletal muscle. Additionally, LASSBio-2129 improved insulin sensitivity in the dexamethasone-induced insulin resistance model, with effects comparable to sitagliptin. Conclusions: The combined pharmacological, docking, and ADMET analyses identified LASSBio-2129 as aldose reductase inhibitor candidate and glucokinase activator. Its ability to improve glucose tolerance, enhance glycogen storage, and increase GLUT4 expression highlights its potential as a promising molecule for the treatment of type 2 diabetes mellitus. Full article

Glioblastoma (GBM) is one of the deadliest types of cancer, characterized by a short life expectancy after diagnosis, mostly related to therapy resistance and recurrence. GBM stem-like cells (GSCs) reside within the tumor and contribute to these features; therefore, finding drugs that specifically target such cells holds promise to halt GBM progression. The primary objective of this work is to comprehensively review and discuss the potential of hard drug repurposing to target GSCs. Several studies evaluating drugs showing anti-GSC activity, originally approved for non-cancer indications, were identified. These mainly included antidiabetics (e.g., Metformin, Phenformin, and Sitagliptin), antihypertensives (e.g., Nicardipine, Doxazosin, and Prazosin), antimicrobials (e.g., Pyrvinium pamoate, Flubendazole, and Clofazimine), and central nervous system-acting drugs (e.g., Chlorpromazine, Fluvoxamine, and Disulfiram). Relevant candidates include those that disrupt GSC metabolism, namely impairing mitochondrial function, such as Metformin, Chlorpromazine, and Pyrvinium pamoate. Multiple signaling pathways may be involved, namely the Wnt, PI3K/AKT, and STAT3 pathways, among others. Also significant were those drugs tested in combination, resulting in increased sensitivity to Temozolomide (TMZ), the standard pharmacological treatment available for GBM. Some repurposed agents, such as Disulfiram and Metformin, have already reached clinical testing, although none have yet been incorporated into clinical practice. Importantly, major translational barriers remain, like limited blood–brain barrier penetration and the lack of robust clinical trials. In conclusion, drug repurposing is an affordable and suitable strategy to target GSCs, impairing cell viability, reducing stemness, and enhancing their sensitivity to TMZ, which has potential that should be further explored to improve patients’ clinical outcomes. Full article