Search Results (946)

Angiogenesis, the formation of new blood vessels from existing vasculature, is regulated by a balance between pro- and anti-angiogenic factors. In adults, this process typically occurs in response to inflammation, wound healing, and neoplastic growth. Uniquely, the female reproductive system undergoes cyclical and repetitive angiogenesis with folliculogenesis, decidualization, implantation, and embryo development throughout the reproductive cycle. Ovarian angiogenesis involves a coordinated network of signaling pathways and molecular factors. Vascular endothelial growth factor (VEGF) is the primary driver of this process, supported by other regulators such as fibroblast growth factor (FGF) and hypoxia-inducible factor (HIF). Understanding the molecular mechanisms that govern ovarian angiogenesis is essential for developing new diagnostic and therapeutic approaches in reproductive medicine. Vascular dysfunction and impaired angiogenesis are key contributors to various ovarian disorders and infertility, including polycystic ovary syndrome (PCOS). Therefore, in-depth studies of ovarian vascularization are crucial for identifying the pathophysiology of these conditions and guiding the development of effective treatments. Advancing knowledge in this area holds significant potential for innovation in both medicine and biotechnology. Full article

Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), remain major causes of morbidity and mortality, yet no targeted pharmacological therapy is available. Excessive neutrophil and macrophage infiltration drives reactive oxygen species (ROS) production and cytokine release, leading to alveolar–capillary barrier disruption and fatal respiratory failure. Methods: We applied an integrative multi-omics strategy combining single-cell transcriptomics, peripheral blood proteomics, and lung tissue proteomics in a lipopolysaccharide (LPS, 10 mg/kg)-induced mouse ALI model to identify key signaling pathways. Harpagide, an iridoid glycoside identified from our natural compound screen, was evaluated in vivo (40 and 80 mg/kg) and in vitro (0.1–1 mg/mL). Histopathology, oxidative stress markers (SOD, GSH, and MDA), cytokine levels (IL-6 and IL-1β), and signaling proteins (HIF-1α, p-PI3K, p-AKT, Nrf2, and HO-1) were quantitatively assessed. Direct target engagement was probed using surface plasmon resonance (SPR), the cellular thermal shift assay (CETSA), and 100 ns molecular dynamics (MD) simulations. Results: Multi-omics profiling revealed robust activation of HIF-1, PI3K/AKT, and glutathione-metabolism pathways following the LPS challenge, with HIF-1α, VEGFA, and AKT as core regulators. Harpagide treatment significantly reduced lung injury scores by ~45% (p < 0.01), collagen deposition by ~50%, and ROS accumulation by >60% relative to LPS (n = 6). The pro-inflammatory cytokines IL-6 and IL-1β were reduced by 55–70% at the protein level (p < 0.01). Harpagide dose-dependently suppressed HIF-1α and p-AKT expression while enhancing Nrf2 and HO-1 levels (p < 0.05). SPR confirmed direct binding of Harpagide to HIF-1α (KD = 8.73 µM), and the CETSA demonstrated enhanced thermal stability of HIF-1α. MD simulations revealed a stable binding conformation within the inhibitory/C-TAD region after 50 ns. Conclusions: This study reveals convergent immune–microenvironmental regulatory mechanisms across cellular and tissue levels in ALI and demonstrates the protective effects of Harpagide through multi-pathway modulation. These findings offer new insights into the pathogenesis of ALI and support the development of “one-drug, multilayer co-regulation” strategies for systemic inflammatory diseases. Full article

Pubertal molting represents a pivotal transition in the life cycle of crustaceans, marking the shift from somatic growth to reproductive development. In mud crabs, mating is known to facilitate this process, yet the molecular mechanisms remain poorly understood. Here, we applied full-length transcriptome sequencing to characterize changes in gene expression and alternative splicing (AS) across post-mating ovarian development. AS analysis revealed extensive transcript diversity, predominantly alternative first exon (AF) and alternative 5′ splice site (A5) events, enriched in genes linked to chromatin remodeling, protein regulation, and metabolism, underscoring AS as a fine-tuning mechanism in ovarian development. Comparative analyses revealed profound molecular reprogramming after mating. In the UM vs. M1 comparison, pathways related to serotonin and catecholamine signaling were enriched, suggesting early neuroendocrine regulation. Serotonin likely promoted, while dopamine inhibited, oocyte maturation, indicating a potential “inhibition–activation” switch. In the UM vs. M3 comparison, pathways associated with oxidative phosphorylation, ATP biosynthesis, and lipid metabolism were upregulated, reflecting heightened energy demands during vitellogenesis. ECM-receptor interaction, HIF-1, and IL-17 signaling pathways further pointed to structural remodeling and tissue regulation. Enhanced antioxidant defenses, including upregulation of SOD2, CAT, GPX4, and GSTO1, highlighted the importance of redox homeostasis. Together, these findings provide the first comprehensive view of transcriptional and splicing dynamics underlying post-mating ovarian maturation in Scylla paramamosain, offering novel insights into the molecular basis of crustacean reproduction. Full article

Cervical cancer (CC) represents a major public health concern, ranking as the fourth most frequently diagnosed cancer and one of the leading causes of cancer-related mortality among middle-aged women worldwide. CC is caused by persistent infection with high-risk human papillomaviruses (HR-HPVs), with HPV 16 being the cause of more than 50% of CC cases. In this study, the exometabolome of the HPV 16-positive cell lines SiHa and Ca Ski, as well as the HPV 16-negative control cell line C-33 A, was evaluated. The exometabolome was validated through molecular signatures using a transcriptomic approach to identify genes encoding cellular metabolic enzymes. The exometabolome was analyzed using ¹H nuclear magnetic resonance spectroscopy (¹H-NMR). Exometabolomic profiles were subsequently compared through both multivariate and univariate statistical analyses to identify significant differences between cell lines. Molecular signatures were analyzed from the GSE9750 dataset obtained from the GEO database. Exometabolic profiling of the HPV 16 positive cell lines showed higher concentrations of leucine, isoleucine, valine, lysine, methionine, glutamine, ornithine, choline, glucose, and tryptophan. An expression analysis showed increased expression of enzymes involved in amino acid synthesis, the tricarboxylic acid cycle, glycolysis, the pentose phosphate pathway, galactose metabolism, and HIF-1α. These data suggest metabolites and metabolism-associated genes that can be used as non-invasive, stable diagnostic and prognostic biomarkers, as well as therapeutic targets for CC in the presence of HPV 16. Full article

Background and Objectives: Cardiovascular disease remains a leading cause of mortality in Diabetes mellitus (DM), where chronic hyperglycemia induces oxidative stress, mitochondrial dysfunction, and hypoxia in cardiomyocytes. Liraglutide (Lir), a glucagon-like peptide-1 receptor agonist, is widely used for type 2 DM management and has been shown to exert cardioprotective and antioxidant effects. This study aimed to evaluate whether Lir mitigates hyperglycemia-induced oxidative and hypoxic stress in H9c2 cardiomyoblasts while preserving cellular ultrastructure. Materials and Methods: H9c2 cells were cultured under normoglycemic (5.5 mM) or hyperglycemic (30 mM) conditions, with or without Lir. Cell viability was assessed using MTT assay. Ultrastructural changes were examined by transmission electron microscopy (TEM). Hypoxia-inducible factor-1α (HIF-1α), lipid peroxidation markers (LOOH, MDA), advanced oxidation protein products (AOPP), and total antioxidant capacity (TAC) were quantified by spectrophotometric assays. Results: MTT assays revealed that Lir significantly improved cell viability under hyperglycemic conditions and the EC₅₀ was 1.05 ± 0.06 μM after 48 h of treatment. Under HG, HIF-1α, lipid hydroperoxides (LOOH), malondialdehyde (MDA) and advanced oxidation protein products (AOPP) increased and total antioxidant capacity (TAC) decreased (p < 0.001, for all); Lir significantly reversed these changes, restoring values to near-NG levels. Ultrastructural analysis of HG + Lir-treated cells revealed reduced granules, increased vacuolization, and slight rough endoplasmic reticulum dilatation, though mitochondria appeared normal. Conclusions: Lir significantly attenuated oxidative stress and cellular injury in cardiomyocytes under hyperglycemic conditions, improving viability, modulating HIF-1α expression, and restoring antioxidant balance. These findings support a dual role for Lir in diabetic cardiomyopathy: glucose-independent cytoprotection and regulation of mitochondrial and hypoxia pathways, highlighting its therapeutic potential beyond glycemic control. Full article

Reduced oxygen availability, or hypoxia, is an environmental stress factor that modulates cellular and systemic functions. It plays a significant role in both physiological and pathological conditions, including tissue regeneration, where it influences angiogenesis, metabolic adaptation, inflammation, and stem cell activity. Hypoxia-inducible factors (HIFs) orchestrate these responses by activating genes that promote survival and repair, although HIF-independent mechanisms, particularly those related to mitochondrial function, are also involved. Depending on its duration and severity, hypoxia may exert either beneficial or harmful effects, ranging from enhanced regeneration to fibrosis or maladaptive remodeling. This review explores the systemic and cellular effects of acute, chronic, intermittent, and preconditioning hypoxia in the context of tissue regeneration. Hypoxia-driven responses are examined across tissues, organs, and complex structures, including the heart, muscle, bone, vascular structures, nervous tissue, and appendages such as tails. We analyze findings from animal models and in vitro studies, followed by biomedical and pharmacological strategies designed to modulate hypoxia and their initial exploration in clinical settings. These strategies involve regulatory molecules, signaling pathways, and microRNA activity, which are investigated across species with diverse regenerative capacities to identify mechanisms that may be conserved or divergent among taxa. Lastly, we emphasize the need to standardize hypoxic conditions to improve reproducibility and highlight their therapeutic potential when precisely controlled. Full article

Periodontitis is a common inflammatory disease affecting the supporting structures of teeth. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, is known for its therapeutic properties in various diseases, including periodontitis. This study aims to identify the gene targets of EGCG and investigate its potential in modulating molecular pathways associated with periodontitis. The potential gene targets of EGCG were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction databases, while genes associated with periodontitis were sourced from GeneCards and Gene Expression Omnibus (GEO) datasets. By overlapping the two datasets, ten common target genes were identified. To explore their functional relevance, enrichment analyses such as Gene Ontology (GO) and REACTOME pathway mapping were conducted. Protein–protein interaction (PPI) networks were then generated, and further analyses involving molecular docking and molecular dynamics (MD) simulations were carried out to evaluate the binding affinity and structural stability of EGCG with the selected target proteins. Ten common genes (MMP2, MMP14, BCL2, STAT1, HIF1A, MMP9, MMP13, VEGFA, ESR1, and PPARG) were identified. PPI network and GO and pathway analyses identified the promising hub genes as ESR1, MMP2, MMP9, MMP13, and STAT1 and which highlighted roles in tissue development, extracellular matrix remodeling, and signaling pathways such as interleukin and matrix metalloproteinase activities. Molecular docking and MD simulations revealed strong binding interactions between EGCG and key proteins (ESR1, MMP2, MMP9, MMP13, and STAT1), with favorable binding energies and stable complexes. Among these, ESR1 and MMP13 exhibited the most favorable docking scores and stability in molecular dynamics simulations and MM–PBSA calculations. This study provides valuable insights into the molecular mechanisms of EGCG in periodontitis treatment. The findings suggest that ESR1 and MMP13 are the most promising targets for EGCG, supported by strong binding interactions and stable conformations in simulations. These results offer a foundation for further experimental studies and potential therapeutic applications of EGCG in managing periodontitis. Full article

Isocitrate dehydrogenase 1 (IDH1) mutations are key drivers of glioma biology, influencing tumor aggressiveness and treatment response. To elucidate their molecular impact, we performed proteome analysis on patient-derived (PD) and U87MG glioma cell models with either mutant or wild-type IDH1. We quantified over 6000 protein groups per model, identifying 1594 differentially expressed proteins in PD-AS (IDH1_MUT) vs. PD-GB (IDH1_WT) and 904 in U87_MUT vs. U87_WT. Both IDH1_MUT models exhibited enhanced MHC antigen presentation and interferon signaling, indicative of an altered immune microenvironment. However, metabolic alterations were model-dependent: PD-AS cells shifted toward glycolysis and purine salvage, while U87_MUT cells retained oxidative phosphorylation, potentially due to D2-hydroxyglutarate (2OHG)-mediated HIF1A stabilization. We also observed a predominance of downregulated DNA repair proteins in IDH1_MUT models, particularly those involved in homologous recombination. In contrast, RB1 and ASMTL were strongly upregulated in both IDH1_MUT models, implicating them in DNA repair and cellular stress responses. We also found distinct expression patterns of proteins regulating histone methylation in IDH1_MUT cells, favoring increased methylation of H3K4, H3K9, and H3K36. A key driver of this may be the upregulation of SETD2 in PD-AS, an H3K4 and H3K36 trimethyltransferase linked to the recruitment of HIF1A as well as DNA mismatch repair proteins. This study uncovers candidate biomarkers and pathways relevant to glioma progression and therapeutic targeting, but also underscores the complexity of predicting glioma pathogenesis and treatment responses based on IDH1 mutation status. While proteome profiling provides valuable insights, a comprehensive understanding of IDH1_MUT gliomas will likely require integrative multi-omics approaches, including DNA/RNA methylation profiling, histone and protein post-translational modification analyses, and targeted DNA damage and repair assays. Full article

Glioblastoma (GBM) is an aggressive brain tumor with a highly immunosuppressive microenvironment that promotes tumor progression and therapy resistance. Tumor-associated macrophages (TAMs), comprising up to 50% of the tumor mass, are recruited via chemokine axes such as CCL2/CCR2, CX3CL1/CX3CR1, and CXCL12/CXCR4 and adopt an M2-like immunosuppressive phenotype, facilitating immune escape and angiogenesis. Key signaling pathways, including CSF1R, STAT3, NF-κB, PI3K/Akt, and HIF-1α, regulate TAM function, making them promising therapeutic targets. Strategies such as TAM depletion, reprogramming, and immune checkpoint blockade (PD-1/PD-L1, and CD47-SIRPα) have shown potential in preclinical models. Emerging approaches, including CAR-macrophage (CAR-M) therapy, nanotechnology-based drug delivery, and exosome-mediated modulation, offer new avenues for intervention. However, clinical translation remains challenging due to GBM’s heterogeneity and adaptive resistance mechanisms. Future research should integrate multi-omics profiling and AI-driven drug discovery to refine TAM-targeted therapies and improve patient outcomes. This review provides a comprehensive analysis of TAM-mediated immune regulation in GBM and explores evolving therapeutic strategies aimed at overcoming its treatment barriers. Full article

HIV/AIDS remains a major global health challenge, with immune dysfunction, chronic inflammation, and comorbidities sustained by latent viral reservoirs that evade antiretroviral therapy. Euclea natalensis, a medicinal plant widely used in Southern African ethnomedicine, remains underexplored for its potential against HIV. An integrative systems pharmacology and molecular modeling framework was employed, including ADME profiling, target mapping, PPI network analysis, GO and KEGG pathway enrichment, BA-TAR-PATH analysis, molecular docking, MD simulations, and MM/GBSA calculations, to investigate the mechanistic roles of E. natalensis phytochemicals in HIV pathogenesis. Sixteen phytochemicals passed ADME screening and mapped to 313 intersecting host targets, yielding top ten hub genes with GO annotations in immune-metabolic, apoptotic, and nuclear signaling pathways. KEGG analysis revealed the enrichment of HIV-relevant pathways, including Th17 cell differentiation (hsa04659), PD-L1/PD-1 checkpoint (hsa05235), IL-17 signaling (hsa04657), HIF-1 signaling pathway (hsa04066), and PI3K-Akt (hsa04151). Lead phytochemicals, diospyrin and galpinone, strongly targeted key hub proteins (NFκβ1, STAT3, MTOR, HSP90AA1, and HSP90AB1), demonstrating favorable binding affinities, conformational stability, and binding free energetics compared to reference inhibitors. E. natalensis phytochemicals may modulate Th17 differentiation, HIV latency circuits, and comorbidity-linked signaling by targeting multiple host pathways, supporting their potential as multi-target therapeutic candidates for adjunct HIV/AIDS treatment and immunotherapy. Full article

Background: Hypoxia-induced glycolysis represents a hallmark of colorectal cancer (CRC) progression and contributes significantly to therapeutic resistance. Curcumol, a natural sesquiterpenoid derived from Curcumae Rhizoma, has demonstrated promising anti-tumor properties. However, its impact on metabolic reprogramming under hypoxic conditions remains largely undefined. Objective: The objective of this study was to elucidate the potential of Curcumol in inhibiting glycolytic reprogramming and impede CRC progression via regulation of the VHL/HIF-1α signaling pathway. Methods: CRC cells and orthotopic mouse models were treated with Curcumol under chemically induced hypoxic conditions. Metabolic alterations were evaluated using Seahorse extracellular flux analysis, Western blot analysis, quantitative real-time PCR (qRT-PCR), immunohistochemistry (IHC) and co-immunoprecipitation (Co-IP). Functional validation of glycolysis and epithelial–mesenchymal transition (EMT) phenotypes was conducted through in vitro and in vivo assays. Results: Curcumol inhibited HIF-1α-mediated metabolic reprogramming by upregulating VHL expression, thereby promoting HIF-1α degradation. This effect led to the downregulation of key glycolytic genes (HK2, LDHA, and GLUT1), decreased glycolytic flux, and lactate production, ultimately suppressing CRC cell proliferation and invasion. The anti-tumor efficacy of Curcumol was validated in both in vitro and in vivo models. Moreover, Curcumol effectively reversed the hypoxia-induced epithelial–mesenchymal transition (EMT) phenotype, suggesting that its metabolic regulatory effects may contribute to reduced metastatic potential. Conclusions: Curcumol suppresses glycolysis and CRC progression by activating the VHL/HIF-1α signaling axis. These findings underscore the potential of Curcumol as a natural metabolic regulator capable of reversing tumor metabolic reprogramming, offering a promising therapeutic strategy for CRC treatment. Full article

Several microRNAs (miRNAs) are key influencers of tumor microenvironment (TME) cell plasticity, regulating the progression of various tumor types such as glioblastoma (GBM). Differential expressions of miR-27a-3p and miR-155-5p in GBM cells and biopsies have already been described as markers of tumor subtype and progression. We aimed to evaluate the cellular and molecular impacts of inhibiting these two overexpressed miRNAs in GBM cell lines. A172 cells were transfected with miR-27a-3p and miR-155-5p inhibitors, and the effects on cellular processes and the expression of malignancy-related genes were analyzed by flow cytometry and qPCR, respectively. Thus, several cellular characteristics in A172 cells were modulated; however, only the inhibition of miR-27a-3p resulted in apoptosis, reduced glucose uptake, and a decrease in mitochondrial membrane potential. Both inhibitors modulated metabolic and immunological targets, negatively regulating genes in the glycolysis pathway and modulating other metabolic pathways involving glutamine and fatty acids, for example. Additionally, it modulates the TGF-β pathway, which can influence the GBM microenvironment due to its immunosuppressive role in advanced tumors. miR-27a-3p appears to be a pivotal factor in the functional duality of TGF-β and its interaction with HIF1A in the hypoxic tumor environment, modulating SMAD partners or TGF-β pathway inhibitors. Here, we demonstrate the importance of inhibiting overexpressed miRNAs, particularly miR-27a-3p, in modulating key pathways for tumor cell survival. The results of this work provide new insights into potential targets for immune-metabolic interactions in the TME and their implications for tumorigenesis, shedding light on new therapeutic approaches for GBM. Full article

Background and Objectives: Endometrial adenocarcinoma is among the most prevalent malignancies of the female reproductive system, and therapeutic options remain limited, particularly in advanced stages. In recent years, natural agents, especially flavonoids, have gained considerable interest for their capacity to enhance the effectiveness of chemotherapeutic drugs and modulate tumor-related molecular mechanisms. Hesperidin, a citrus-derived flavonoid, is recognized for its antioxidant and anti-inflammatory effects, while Gemcitabine, a nucleoside analog, is widely used in cancer treatment. Investigating their combined effects on endometrial carcinoma cells could yield novel insights into multimodal therapeutic development. This current study aimed to assess the impact of Hesperidin (Hes) and Gemcitabine (Gem) on ISHIKAWA cells, a human endometrial adenocarcinoma model, with particular attention to pathways associated with hypoxia, angiogenesis, apoptosis, and oxidative stress. Materials and Methods: ISHIKAWA cells were treated with varying concentrations of Hes (50–200 µM) and Gem (10–50 nM), either individually or together, for 24 and 48 h. Cell viability was determined using the MTT assay, while apoptosis was measured by Caspase-3/7 activity and NucBlue nuclear staining. Intracellular reactive oxygen species (ROS) generation was quantified via DCFH-DA fluorescence. Expression levels of HIF-1α, VEGF, Bax, Bcl-2, and Caspase-3 were examined by RT-qPCR. Synergistic interactions were analyzed with the Chou–Talalay combination index. Biological enrichment was further explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results: Both Hes and Gem significantly decreased ISHIKAWA cell viability in a concentration- and time-dependent manner (p < 0.001). The combined treatment induced stronger apoptotic effects, as reflected by increased Caspase-3/7 activity and nuclear morphological changes. RT-qPCR demonstrated upregulation of Bax and Caspase-3, together with downregulation of Bcl-2, HIF-1α, and VEGF. While Hes reduced intracellular ROS, Gem elevated it; their combination produced a balanced oxidative response. All dose combinations displayed strong synergism (CI < 1). GO and KEGG enrichment confirmed the involvement of apoptosis-, angiogenesis-, and hypoxia-related pathways. Conclusions: Co-treatment with Hes and Gem exhibits synergistic anticancer activity in endometrial cancer cells by promoting apoptosis, suppressing angiogenesis- and hypoxia-related gene expression, and modulating oxidative stress. This combined therapeutic approach highlights its potential as a promising adjuvant option, warranting further evaluation in in vivo and translational studies. Full article

Background: Breast cancer is the most common cancer among women. Although doxorubicin (DOX) is widely used in its treatment, its dose-dependent toxicity and the development of drug resistance reduce its therapeutic efficacy. Therefore, this study aims to identify a novel anticancer agent that is more effective than DOX, inhibits cancer cell growth, and is less toxic to healthy cells. Methods: The cytotoxic effects of DOX and 2S-series molecules were evaluated on human (MDA-MB-231) and mouse (4T1) TNBC breast cancer cell lines and healthy breast epithelial (hTERT) cells using MTT assays at 48 and 72 h to screen functional similarities and possible differences upon drug/inhibitor treatment. Apoptosis and cell cycle analysis were analyzed by flow cytometry. Gene expression profiles were assessed by qPCR, and binding interactions with Hsp90 were examined via molecular docking. Results: 2S-5 exhibited IC₅₀ values of 6.21 µM (MDA-MB-231) and 7.04 µM (4T1), while 2S-13 showed IC₅₀ values of 7.73 µM and 8.21 µM, respectively. Both compounds demonstrated selective cytotoxicity against cancer cells. Gene expression and pathway analysis revealed that 2S-13 modulated the PI3K-Akt, MAPK, apoptosis, and HIF-1 pathways, showing broader modulation than DOX. Conclusions: 2S-13 appears to be a promising drug candidate, particularly in the MDA-MB-231 cell line. However, the current findings are limited to in vitro models. Further in vivo studies and pharmacokinetic analyses are required to validate its therapeutic potential, assess long-term efficacy and safety, and explore its resistance profile and molecular mechanisms in more detail. Full article

Oral tongue squamous cell carcinoma (OTSCC) is a common type of oral cancer influenced by genetic, epigenetic, and environmental factors like exposure to environmental toxins. These environmental toxins can decrease the effectiveness of established chemotherapy drugs, such as Irinotecan, used in OTSCC treatment. Bioinformatics, drug discovery, and machine learning techniques were employed to investigate the impact of Irinotecan on OTSCC patients by identifying targets and signaling pathways, including those that positively influence protein phosphorylation, protein tyrosine kinase activity, the PI3K-Akt (Phosphatidylinositol 3-kinase- Protein Kinase B) signaling system, cancer pathways, focal adhesion, and the HIF-1 (Hypoxia-Inducible Factor 1) signaling pathway. Later, the protein–protein interactions (PPIs) network, along with twelve cytoHubba approaches to finding the most interacting molecule, was employed to find the important proteins BCL2 and EGFR. Drugs related to BCL2 and EGFR were extracted from the DGIdb database for further molecular docking. Molecular docking revealed that Docetaxel, Paclitaxel, Imatinib, Ponatinib, Ibrutinib, Sorafenib, and Etoposide showed more binding affinity than Irinotecan (i.e., −9.8, −9.6). Of these, Paclitaxel (−10.3, −11.4) and Imatinib (−9.9, −10.4) are common in targeting BCL2 and EGFR. Using these identified candidate genes and pathways, we may be able to uncover new therapeutic targets for the treatment of OTSCC. Furthermore, molecular dynamics (MD) simulations were performed for selected ligand–receptor complexes, revealing stable binding interactions and favorable energetic profiles that supported the docking results and strengthened the reliability of the proposed drug repurposing strategy. Full article