Search Results (9,139)

The failure of therapy in muscle invasive bladder cancer (MIBC) is primarily attributed to tumor heterogeneity and therapy resistance. We propose a novel approach targeting interleukin-13 receptor subunit alpha 2 (IL-13Rα2), which is expressed on bladder cancer (BC) cells but absent in normal urothelial cells. We investigated the therapeutic effects of WPD101a immunotoxin (IL-13-DT390) on IL-13Rα2-expressing BC cells in relation to BC cell phenotype and functional characteristics in vitro using both 2-dimensional (2D) and 3-dimensional (3D) models. Cell phenotype and IL-13Rα2 expression were assessed using flow cytometry, immunofluorescence, and Western blot analysis. The biological effects of WPD101a were evaluated by measuring cell viability and proliferation using the MTT, sulforhodamine B (SRB), CellTiter-Glo and Live/Dead assays. Apoptosis was assessed using Annexin V/propidium iodide (PI) staining, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of CASP genes expression. We found that the reference BC cell lines TCC-SUP, JMSU-1 and UM-UC-3 express IL-13Rα2 at various level in contrast to RT-4, HCV-29 and 5637 cells. Cells expressing IL-13Rα2 were sensitive to WPD101a at lower concentrations in the 2D model (0.1 ng/mL) compared to the 3D model (1.0 ng/mL). IL-13Rα2-negative cells remain resistant to the immunotoxin. WPD101a induces apoptosis in BC cells expressing IL-13Rα2 as confirmed by the presence of apoptotic cells, increase the proportion of cells in the subG1 phase, and by the effector CASP3, CASP7, and initiator CASP8, CASP9 genes expression. This study confirmed receptor-dependent cytotoxic effects of WPD101a and the ability and specificity to inhibit growth and apoptosis induction in MIBC cells expressing IL-13Rα2. Full article

Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related deaths, while its resistance to treatment continues to represent a major therapeutic challenge. In the present study, a series of phenothiazine derivatives, including hybrids containing a 1,2,3-triazole linker and the zidovudine (AZT) fragment, were synthesized and evaluated for their anticancer activity against colorectal cancer cell lines HCT116 and HT-29 as well as non-cancerous BEAS-2B cells. Cytotoxic activity was determined using the Alamar Blue assay, while the mechanisms of action were investigated by flow cytometric analysis of apoptosis, cell cycle progression, and reactive oxygen species (ROS) generation. Additionally, changes in the expression of genes associated with apoptosis, oxidative stress, and DNA damage response were analyzed by RT-qPCR. The obtained results demonstrated that AZT-containing derivatives exhibited stronger anticancer activity than non-conjugated phenothiazine analogs. Compounds A9–A12 induced pronounced apoptosis and significant disturbances in cell cycle progression, particularly in HCT116 cells. Among the analyzed derivatives, compound A9 displayed the most favorable overall biological profile, combining strong proapoptotic and cytotoxic activity with relatively high selectivity toward cancer cells and moderate effects on non-cancerous cells. The results indicate that molecular hybridization of phenothiazine derivatives with the AZT scaffold represents a promising strategy for the development of novel anticancer agents targeting colorectal cancer. Full article

Soil salinity is a major constraint on global wheat productivity, yet the genetic and molecular determinants of root system architecture (RSA) adaptation under salt stress remain poorly characterized. We integrated a genome-wide association study (GWAS) of 566 wheat accessions with comparative RNA-seq transcriptomics to identify the genetic and transcriptional determinants of RSA adaptation under 200 mM NaCl. GWAS identified a candidate locus on chromosome 7B harboring TaIAO, which encodes a protein with predicted aldehyde oxidase-like activity consistent with a role in tryptophan-dependent auxin biosynthesis. Accessions carrying the favorable CC allele exhibited significantly greater root volume retention than those carrying the GG genotype (p < 0.001). Comparative RNA-seq revealed that the salt-tolerant Sarajevo 1 exhibited coordinated transcriptional repression of three distinct modules—cell wall expansion (TaExpansin), auxin redistribution (TaPIN-like), and stress-associated ROS defense (TaPOD1)—whereas the sensitive genotype CI 17260 aberrantly induced or incompletely repressed these modules under stress. ELISA-based IAA quantification, ROS imaging, and qRT-PCR analysis provided independent physiological and transcriptional support for these patterns. These findings support a two-tier adaptive model in which constitutive genetic variation at the TaIAO locus may contribute to a developmental baseline, coupled with coordinated stress-responsive transcriptional repression of energy-consuming modules, providing promising targets for marker-assisted breeding of salt-tolerant wheat. Full article

Autoimmune myocarditis frequently progresses to inflammatory cardiomyopathy through dysregulated immune–stromal interactions. This study employs single-nuclei RNA-sequencing (snRNA-seq) to profile 46,233 cardiac nuclei from the experimental autoimmune myocarditis (EAM) mouse model at four timepoints: day 0 (healthy), day 14 (inflammation), day 21 (acute inflammation), and day 40 (late cardiac remodelling). Single-nuclei RNA profiling identified 18 transcriptionally distinct cell populations. Global cell–cell communication analysis revealed a dramatic peak of intercellular signalling at day 14 (5907 interactions), with fibroblast subpopulations and macrophages as dominant hubs, followed by partial resolution at day 21 (2264 interactions) and renewed remodelling at day 40 (4862 interactions). Subclustering of the macrophage compartment identified five subpopulations: Mac-TLF, Mac-MHCII, Mac-rMHCII, Mac-ResL, and Classical Monocytes. Tissue-resident macrophages (Mac-TLF, CCR2-) dominated at healthy state (~55%) but were rapidly depleted at day 14, coinciding with a dramatic influx of recruited CCR2⁺ macrophages (Mac-rMHCII), which expanded to over 70% of the compartment and maintained dominance through day 40. At inflammation (day 14), the expanded Mac-rMHCII subpopulation displayed a strongly pro-inflammatory signature (Il1b, Ankrd1, Stat2, Parp14, Apoe), and the overall macrophage compartment was enriched for cytokine response, Fc-gamma receptor, and Notch signalling pathways, while downregulating homeostatic and mitochondrial metabolic programmes, potentially contributing to impaired efferocytosis and cardiomyocyte dysfunction. Macrophage-centred communication networks expanded markedly at day 14 (1047 interactions), with resting fibroblasts (FB-R) as the primary signalling partner, driving pro-inflammatory stromal activation marked by upregulation of Ccl2, Ccl7, and Csf2. Intra-macrophage subcluster communication also intensified at this timepoint (447 interactions). These findings delineate the temporal and functional heterogeneity of cardiac macrophages during EAM progression and identify key immune–stromal interactions driving pathological cardiac remodelling. The coexistence of pro-inflammatory and transitional reparative macrophage subsets highlights the limitations of broad immunosuppression and supports precision strategies targeting CCR2-mediated recruitment, the SPP1 signalling axis, and macrophage–fibroblast crosstalk as therapeutic avenues in myocarditis and its progression. Full article

Introduction: Neuroinflammation is a key feature of both Alzheimer’s disease (AD) and glioblastoma, although it leads to different outcomes in each disorder. In AD, chronic activation of microglia and astrocytes by amyloid-β and tau contributes to neuronal injury and cognitive decline. In glioblastoma, tumor cells exploit inflammatory pathways to create an immunosuppressive microenvironment that supports tumor growth. This review compares the shared and distinct neuroinflammatory mechanisms in AD and glioblastoma and highlights their therapeutic relevance. Materials and Methods: This study was conducted as a narrative review based on a PubMed search performed by three reviewers. English-language articles on AD, glioblastoma, and neuroinflammatory pathways were included, covering original studies, reviews, meta-analyses, and experimental and clinical reports. Keywords included neuroinflammation, microglia, astrocytes, tumor-associated macrophages, inflammasomes, NLRP3, NF-κB, HIF-1α, cytokines, blood–brain barrier, and miRNAs. Due to study heterogeneity, findings were synthesized descriptively. Results: AD and glioblastoma share major neuroinflammatory mechanisms, including microglial and astrocytic activation, cytokine signaling, inflammasome activity, blood–brain barrier dysfunction, hypoxia-related changes, and miRNA regulation. In AD, these pathways promote chronic inflammation, synaptic loss, and neurodegeneration, with NLRP3, NF-κB, and M1-like microglial polarization playing central roles. In glioblastoma, similar pathways are redirected toward tumor progression through tumor-associated macrophages, reactive astrocytes, angiogenesis, immune evasion, and therapy resistance. Key overlapping mediators include IL-1β, TNF-α, NF-κB, HIF-1α, GSK-3β, and selected miRNAs. Conclusions: AD and glioblastoma are connected by common neuroinflammatory pathways, but these processes result in neurodegeneration in AD and tumor support in glioblastoma. Understanding these shared and divergent mechanisms may guide the development of biomarkers and targeted therapies focused on microglia, inflammasomes, cytokines, and immune reprogramming in both diseases. Full article

Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein dynamin-related protein 1 (DRP1) promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated “redox-dead” DRP1-C631A knock-in mutant (Drp1^C/A) BM exhibited markedly reduced limb perfusion recovery and CD31⁺ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G⁺ neutrophil accumulation, pro-inflammatory F4/80⁺CD80⁺ M1-like macrophages and reduced anti-inflammatory F4/80⁺CD206⁺ M2-like macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia serum starvation (HSS) rapidly induced NADPH oxidase 2-dependent cytosolic ROS production and DRP1-CysOH formation in wild-type macrophages. In contrast, Drp1^C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK, efferocytosis and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD. Full article

Dipeptidyl peptidase-4 (DPP-4) is a key therapeutic target for type 2 diabetes (T2D). Several synthetic anti-DPP-4 drugs are currently available for the treatment of T2D; however, the need for safe and effective therapies remains unmet due to the side effects associated with existing DPP-4 inhibitors. This study aimed to integrate structure-based and machine learning (ML)-based virtual high-throughput screening to identify natural DPP-4 inhibitors. Random forest, logistic regression, support vector machine (SVM), and multilayer perceptron (MLP) models were trained on DPP-4 IC₅₀ datasets. Among these, the SVM and MLP models achieved high predictive performance, with areas under the curve of 0.928 and 0.923, respectively. Screening of a natural compound database identified 107 compounds for further analysis. Subsequent structure-based screening, using sitagliptin as a positive control, identified sennidin B and doxorubicin hydrochloride as promising candidates with strong binding affinity for DPP-4. Molecular dynamics simulations (200 ns) and MM-PBSA calculations confirmed stable interactions with DPP-4. Further, sennidin B and doxorubicin hydrochloride inhibited DPP-4 activity in a concentration-dependent manner, with estimated IC₅₀ values of 39.39 and 19.78 μM, respectively. Sennidin B also reduced DPP-4 mRNA and protein expression levels in Caco-2 cells. Overall, sennidin B shows promise as a natural DPP-4 inhibitor and warrants further investigation as a potential antidiabetic agent. Full article

Melanoma incidence rates have also been steadily increasing, emphasizing the need for improved prognostic and diagnostic tools with the goal of enhancing patients’ outcomes. Biomarkers in melanoma have emerged as an important component of melanoma management, offering insight into disease progression, tumor biology, and the potential for judging treatment responses. Traditionally, blood and immunohistochemical markers such as lactate dehydrogenase (LDH), S100 calcium-binding protein (S100B), human melanoma black-45 (HMB-45), and SRY-box transcription factor 10 (SOX10) have been widely used in melanoma diagnosis, staging, and monitoring. However, their clinical use has been limited because of their low specificity, especially in patients with early-stage disease. This has led to the development of molecular and genetic biomarkers, including BRAF, NRAS, and KIT mutations, which improved patients’ risk stratification and enabled targeted therapies, and gene expression signature assays such as DecisionDx (Castle Biosciences) and SkylineDx (Merlin) that are already used in clinics to help with surgical decisions and to assess patients’ prognosis. Other circulating biomarkers, including microRNAs, circulating tumor DNA and circulating tumor cells, have been developed to provide minimally invasive approaches to monitor tumor evolution and detect recurrence. However, none of these new approaches are used in clinics due to their low specificity and/or sensitivity. Additionally, nomograms or predictive models have been created using biomarkers and clinicopathologic data to assess patients’ outcomes and survival. While significant progress has been made, the integration of melanoma biomarkers into routine clinical practice remains limited. This review summarizes current advancements in melanoma biomarkers, including traditional serum and immunohistochemical markers, as well as developments in molecular, genetic, circulating, and predictive biomarker approaches. Full article

Background/Objectives: Immune checkpoints are critical regulatory pathways that maintain peripheral tolerance and prevent autoimmunity. Among these, the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis serves as a major inhibitory pathway that terminates T cell responses. While protein-based checkpoint blockade (ICB) targeting this axis has revolutionized clinical cancer therapy, its clinical efficacy is frequently limited by low response rates, immune-related adverse events (irAEs), and the emergence of adaptive resistance. To break through these bottlenecks, genetic interruption has emerged as a high-precision alternative to modulate the PD-1/PD-L1 pathway at the nucleotide level. Methods: A comprehensive systematic review of literature was performed across major databases (PubMed, Web of Science), with a focus on high quality studies published up to 2026. Results: Direct genomic disruption via CRISPR/Cas9 and post-transcriptional silencing through RNA interference can effectively neutralize inhibitory signaling at its source. Recent advances demonstrate that targeting upstream regulatory nodes—including metabolic checkpoints (e.g., lactate metabolism) and biophysical mechanisms (e.g., liquid–liquid phase separation)—provides superior transcriptional control over PD-L1. Furthermore, engineering CAR-T cells with multiplex gene editing (e.g., TCR/B2M/PD-1 knockout) or localized scFv secretion significantly enhances antitumor potency while reducing systemic toxicity. Innovations in organ-targeted lipid nanoparticles and stimuli-responsive biomimetic carriers further address the delivery barriers in solid tumors. Conclusions: Gene therapy provides a high-precision platform for PD-1/PD-L1 modulation, offering a viable strategy to overcome adaptive resistance. Future clinical application depends on the refinement of safer editing tools, such as base editing, and the standardization of intelligent delivery systems to ensure controllable and scalable cancer immunotherapy. Full article

The A3 adenosine receptor (A3AR) is a stress-inducible G-protein-coupled receptor that is selectively upregulated in inflamed, hypoxic, and fibrotic tissues as well as in many malignancies, while remaining weakly expressed in most normal organs. This distinctive expression pattern provides a strong biological basis for pathology-selective pharmacology. Activation of A3AR by highly selective agonists, including piclidenoson (IB-MECA) and namodenoson (Cl-IB-MECA), initiates signaling through Gi proteins and phospholipase C (PLC), which in turn regulate a coordinated network of downstream intracellular pathways, including PI3K/Akt, NF-κB, MAPKs, and Wnt/β-catenin, resulting in suppression of inflammation, inhibition of pathological cell survival, and protection of metabolically stressed tissues. Over the three decades, extensive preclinical studies have demonstrated that A3AR agonism exerts anti-cancer, anti-fibrotic, immunomodulatory, neuroprotective, and organ-protective effects across diverse disease models, including hepatocellular carcinoma, pancreatic cancer, psoriasis, osteoarthritis, metabolic dysfunction-associated steatohepatitis, ischemic stroke, neurodegeneration, ophthalmic disorders, and inherited metabolic syndromes. Importantly, these mechanistic insights have been translated into clinical programs, with piclidenoson and namodenoson demonstrating favorable safety profiles and disease-modifying activity in inflammatory, fibrotic, and oncologic indications. This review integrates molecular, cellular, and translational evidence to highlight A3AR activation as a unifying therapeutic principle for diseases driven by inflammation, oxidative stress, hypoxia, and dysregulated cell survival, positioning selective A3AR agonists as first-in-class agents targeting the A3AR, with broad clinical applicability across multiple disease domains. Full article

Background: Hexavalent chromium (Cr(VI)) is a widespread environmental toxic heavy metal with strong oxidative properties; however, its immunotoxicity and metabolic mechanisms in rabbit spleen remain largely unclear. Methods: In this study, New Zealand rabbits were exposed to 0, 12.5, 25, and 50 mg/L Cr(VI) (as potassium dichromate, K₂Cr₂O₇) via drinking water for four weeks to investigate splenic damage and the underlying molecular pathways. Spleen pathological injury was evaluated by hematoxylin and eosin (H&E) staining, and the distribution of T cells, B cells, and macrophages was assessed by immunohistochemistry. Antioxidant enzyme activities and antioxidant substance levels were determined using ELISA, and the relative mRNA expression of immune factor genes, antioxidant-related genes, and ferroptosis-related genes was quantified by quantitative real-time PCR (qRT-PCR). In addition, the distribution of iron in splenic tissue was detected by enhanced Prussian blue staining. Results: Our results demonstrate that high-dose Cr(VI) significantly inhibited body weight gain, induced lymphocyte atrophy, vacuolization, and widening of intercellular spaces in the splenic white pulp. Furthermore, Cr(VI) reduced T and B lymphocyte populations, promoted macrophage infiltration and inflammatory cytokine gene expression in a concentration-dependent manner, impaired total antioxidant capacity, and led to a decrease in glutathione (GSH) levels in the spleen. Additionally, Cr(VI) exposure increased iron accumulation, activated the ACSL4–NOX lipid peroxidation cascade, and downregulated GPX4 expression, ultimately triggering ferroptosis. Conclusions: These findings reveal that Cr(VI) causes splenic immune injury by disrupting oxidative homeostasis and inducing ferroptosis, providing novel insights for evaluating immunotoxicity and identifying metabolic targets under Cr(VI) pollution. Full article

Vein graft restenosis is a leading cause of long-term failure after coronary artery bypass grafting (CABG), driven by maladaptive vascular smooth muscle cell (VSMC) responses to arterialization-induced inflammation. The key molecular mediators of this pathological remodeling, however, remain incompletely defined. Here, we integrated multi-omics analyses of human and canine vein graft specimens with in vitro functional assays to identify tenascin-C (TNC)—a matricellular extracellular matrix protein—as a critical regulator of VSMC dysfunction. TNC was specifically enriched in a synthetic, pro-inflammatory VSMC subpopulation. Pro-inflammatory stimuli potently induced TNC expression, which was functionally linked to VSMC phenotypic modulation, hyperproliferation, and enhanced migration. Mechanistically, TNC acts upstream of NF-κB signaling; siRNA-mediated TNC knockdown significantly reduced nuclear p65 protein levels and attenuated inflammatory responses. Our integrated computational and experimental data suggest that TNC, NF-κB, and TNF-α function within a sequential pro-inflammatory signaling cascade that sustains vascular inflammation and promotes neointimal hyperplasia. These findings reposition TNC from a passive structural component to an active driver of vascular pathology and highlight the TNC–NF-κB axis as a candidate target for therapeutic intervention to improve vein graft patency. Full article

The proliferation of Unmanned Aerial Vehicles (UAVs) in various applications has created a pressing need for robust and efficient communication systems. Fifth-generation (5G) networks can support UAV connectivity through high bandwidth and low-latency communication; however, rapid three-dimensional UAV mobility creates handover-management challenges that can increase signalling overhead, service interruption, and Quality of Service (QoS) degradation. This paper presents an integrated framework that combines LSTM-based multi-UAV trajectory prediction with proactive handover optimization using an Advantage Actor–Critic (A2C) Deep Reinforcement Learning (DRL) agent. The LSTM predictor is evaluated on a real-world UAV trajectory dataset and reports a root mean square error (RMSE) of 4.37 m over a 5 s prediction horizon after conversion to a local East–North–Up coordinate frame. A lightweight simulation-level coordination mechanism is included to reduce simultaneous target-cell contention among multiple UAVs; it is not claimed as a new standardized 3GPP signalling procedure. Handover performance is evaluated by replaying 180 held-out flight trajectories in a controlled 5G simulation across ten independent random seeds. Under these stated assumptions, the proposed framework achieves a handover success rate of $94.2\pm 0.8$%, an average SINR of $15.8\pm 0.2$ dB, a handover delay of $45.2\pm 1.1$ ms, and a handover frequency of $0.85\pm 0.05$ HOs/min, outperforming the tuned 3GPP A3, reactive SINR, and CASH baselines in the reported simulation results (Wilcoxon signed-rank test, $p<0.01$, Bonferroni-corrected). The experimental setup is described in detail to support methodological transparency and facilitate future replication, but the handover results should be interpreted as simulation-based evidence rather than live-network validation. Full article

Blue honeysuckle (Lonicera caerulea L.) is a polyphenol-rich berry increasingly recognized as a functional food ingredient for postprandial glycemic management. However, it remains unclear whether its polyphenols can modulate intestinal glucose transport in addition to inhibiting carbohydrate-digesting enzymes. In this study, blue honeysuckle polyphenol extract (BHPE) was characterized by UPLC-QTOF-MS/MS, and its effects on α-glucosidase activity and intestinal glucose transport were evaluated using enzyme kinetics, fluorescence quenching, molecular docking, and differentiated Caco-2 monolayers. A total of 24 phenolic compounds were tentatively identified, with anthocyanins and chlorogenic acid derivatives as the major constituents. BHPE exhibited a mixed-type, static-quenching inhibition of α-glucosidase (IC₅₀ = 75.05 μg/mL). Furthermore, molecular docking revealed that key constituents, including cyanidin-3-O-glucoside, chlorogenic acid, and proanthocyanidin B1, bind the enzyme via hydrogen bonding and hydrophobic interactions. In Caco-2 cell monolayers, BHPE reduced glucose transport by up to 51.56% under simulated postprandial conditions and coordinately downregulated SGLT1 and GLUT2 mRNA expression to 0.58- and 0.51-fold, respectively. These findings extend the bioactivity profile of blue honeysuckle polyphenols from enzyme-level inhibition to functional regulation at the intestinal epithelial barrier, highlighting their potential as multi-target natural ingredients for the attenuation of postprandial hyperglycemia. Full article

Melanoma exhibits pronounced metabolic plasticity and mitochondrial dependency, contributing to therapeutic resistance and tumor progression. Targeting mitochondrial function therefore represents a promising anticancer strategy. 2-Aminoethyl dihydrogen phosphate (2-AEH₂P), a bioactive phosphomonoester, has demonstrated antiproliferative potential, while metformin, a clinically established antidiabetic drug, acts as a mitochondrial complex I inhibitor and metabolic modulator. This study investigated the cytotoxic and mechanistic effects of 2-AEH₂P and metformin hydrochloride, individually and in combination, in human (SK-MEL-28) and murine (B16-F10) melanoma models, using non-tumorigenic fibroblasts (FN1 and L929) as controls. Cell viability, proliferation dynamics, cell-cycle distribution, mitochondrial membrane potential (ΔΨm), and apoptosis-associated markers were evaluated by flow cytometry. 2-AEH₂P reduced melanoma cell viability and proliferation while inducing G2/M accumulation, DNA fragmentation, mitochondrial depolarization, increased cytochrome c release, caspase-3 and caspase-8 activation, upregulation of p53 and Bad, and downregulation of Bcl-2. Metformin alone exerted moderate cytotoxic and pro-apoptotic effects. Notably, combined treatment markedly potentiated mitochondrial depolarization and intrinsic apoptotic signaling in melanoma cells, significantly lowering IC₅₀ values and enhancing caspase activation and cytochrome c release. Bliss independence analysis demonstrated synergistic interaction in SK-MEL-28 and B16-F10 cells. Although interaction scores indicated synergy in one fibroblast model, absolute cytotoxicity remained lower than in melanoma cells. These findings demonstrate that metabolic co-targeting with metformin enhances mitochondrial dysfunction-associated apoptotic signaling in melanoma cells, supporting a drug repositioning strategy aimed at exploiting mitochondrial vulnerability in metabolically adaptable tumors. Full article