Search Results (13,420)

Background: Chemoresistance is an existing challenge faced in the treatment of the hairy cell leukemia variant (HCL-v). Classical hairy cell leukemia (HCL-c) is very sensitive to the standard of care with purine nucleoside analogs (PNAs) cladribine (cDa) and pentostatin. However, almost half of these patients eventually become less sensitive to chemotherapy and relapse. HCL-variant (HCL-v) is a biologically distinct entity from HCL-c that is not sensitive to frontline PNA therapy, and this treatment is not recommended for these patients. To address these treatment challenges, we investigated the role of B-cell activating factor (BAFF) in promoting HCL-v cell chemoresistance. Methods: Flow cytometry and quantitative PCR were used to measure the levels of BAFF and its receptors. To determine BAFF activated pathways in HCL-c and HCL-v, the Bonna-12 HCL-c cell line or HCL-v patient-derived cancer cells were stimulated with recombinat BAFF and activation of common BAFF-activated pathways, including the nonclassical nuclear factor kappa B (NF-κB) pathway, the Extracellular Signal-Regulated Kinase (Erk) and phosphatidylinositol-3 (PI-3) kinase (PI3K)/AKT serine/threonine kinase (AKT) pathways were measured by western blotting. To test whether BAFF signaling promotes chemoresistance in HCL-v, we stimulated patient-derived HCL-v cells with BAFF and performed RNA sequencing. Lastly, to confirm the functional implications of BAFF signaling in HCL-v, we treated patient-derived HCL-v cells with exogenous BAFF before treatment with cladribine. Results: We found that HCL-v patient-derived cancer cells express receptors of BAFF at varying degrees and express relatively lower levels of membrane-bound BAFF ligand expression. BAFF stimulation of these cells resulted in substantial activation of the nonclassical NF-κB pathway, which is known to promote anti-apoptotic and pro-survival effects in B-cell cancers. Conversely, in the Bonna-12 cell line, we observed constitutive activation of the nonclassical NF-κB pathway. Through RNA sequencing, we found that BAFF upregulates a myriad of genes that are known to promote chemoresistance in various cancers, including IL1, CXCL1/2, CXCL5, CXCL8, TRAF3, and PTGS2. Lastly, we found that BAFF protects these cells from cladribine-induced cell death in vitro. Conclusions: We conclude that BAFF provides chemo-protection in HCL-v cells by activating nonclassical NF-κB signaling, which results in the upregulation of multiple pro-survival or anti-apoptotic genes. Our results highlight an important role of BAFF in HCL-v resistance to chemotherapy and suggest that the BAFF blockade may enhance the chemosensitivity to PNAs in drug-resistant HCL-v patients. Full article

Cutaneous squamous cell carcinoma (CSCC) is one of the most common non-melanoma skin cancers, and particularly challenging to treat in advanced or metastatic stages. Traditional therapies, including chemotherapy and radiation, often result in limited efficacy and severe side effects. Cosibelimab, a fully human monoclonal antibody targeting PD-L1, has emerged as a promising immunotherapy for advanced CSCC. In this review, we evaluate the therapeutic potential of cosibelimab by analyzing its mechanism of action, clinical trial data, and its role compared to other PD-1/PD-L1 inhibitors, such as pembrolizumab and cemiplimab. We synthesized the available preclinical and clinical data on cosibelimab, focusing on published Phase I and II trial results involving 76 patients. Objective response rates (ORRs), progression-free survival (PFS), overall survival (OS), and safety profiles were compared between cosibelimab, pembrolizumab, and cemiplimab. Mechanistic insights into cosibelimab’s dual action, including PD-L1 blockade and antibody-dependent cellular cytotoxicity (ADCC), were also explored. Phase II trials demonstrated an ORR of 47.5%, with a median PFS of 12.9 months in advanced CSCC patients. Cosibelimab demonstrated a favorable safety profile, with predominantly mild to moderate adverse events. Comparative analysis with pembrolizumab and cemiplimab showed similar efficacy, although long-term survival data for cosibelimab is still emerging. Given its efficacy and safety, cosibelimab holds promise not only as a monotherapy but also for future exploration in combination regimens and broader oncologic indications. Future trials are required to validate its long-term outcomes, including overall survival, and to explore its use in combination therapies and neoadjuvant/adjuvant settings. Full article

Background: Anti-glomerular basement membrane (anti-GBM) nephritis is mediated by autoantibodies and may progress to end-stage renal disease. Although its pathogenesis is not completely understood, dendritic cells (DCs) have been reported to play an important role in this process. Hypoxia-inducible factor-2α (HIF-2α) has been reported to have a regulatory effect on DCs under hypoxic conditions, while no research has investigated its role in autoimmune nephritis. Methods: Anti-GBM nephritis was induced in CD11c-specific HIF-2α-deficient and WT mice using nephrotoxic serum (NTS). All mice were divided into four groups: (i) WT+PBS, (ii) CD11c-Cre⁺ Hif2α^fl/fl+PBS, (iii) WT+NTS and (iv) CD11c-Cre⁺ Hif2α^fl/fl+NTS. Seven days after induction, renal function, immune cell infiltration and the expression levels of genes in the renal cortex were assessed in each group. Results: On day 7, the levels of serum creatinine and blood urea nitrogen and the urine albumin-to-creatinine ratio were lower for mice with DC-specific deletion of HIF-2α compared with their WT counterparts (p < 0.05). Histopathological analysis showed that there was less crescent formation in the renal cortex with conditional HIF-2α knockout, and the infiltration of DCs and macrophages was also suppressed (p < 0.05). Genes related to antigen processing and presentation were found to be expressed differentially between the two groups, and the activation of the MAPK pathway was affected (p < 0.05). Western blot analysis validated that HIF-2α knockout inhibited the phosphorylation of p38 MAPK (p < 0.05). Conclusions: In this study, we observed a pro-inflammatory effect of HIF-2α in DCs in early anti-GBM nephritis, and the results suggested a regulating effect of HIF-2α on p38 MAPK pathways. Full article

Introduction: Recent data indicate that approximately 10–20% of patients with severe asthma (SA) receiving benralizumab (BENRA) do not achieve the desired outcomes. Emerging evidence suggests that clinical remission (CRem) is possible with biologics, warranting investigations into predictive factors. Methods: In this retrospective, single-center study, we analyzed 103 SA patients treated with BENRA for 12 months. CRem was defined as meeting four criteria: no exacerbations requiring oral corticosteroids (OCSs), discontinuation of chronic OCS therapy, improvement in FEV1 ≥100 mL, and an ACQ score < 1.5. Logistic regression identified predictors of remission. Results: After 12 months, 33% of patients achieved CRem, while 10% discontinued treatment due to lack of improvement. BENRA reduced the annual exacerbation rate from a median of 2 to 0 (p < 0.0001) and eliminated OCS use in 80% of patients. Lung function improved significantly, with a +13.5% predicted increase in FEV1 (p < 0.0001). Asthma control also improved, with ACQ scores decreasing from 3.2 to 1.5 (p < 0.0001) and mini-AQLQ scores increasing from 3.4 to 5.0 (p < 0.0001). Key predictors of remission included baseline eosinophil count ≥740 × 10³/μL (OR = 3.91, p = 0.02), SA duration (OR = 0.90, p = 0.02), baseline quality of life (OR = 2.18, p = 0.04), and pre-treatment FEV1 (OR = 1.07, p = 0.005). The logistic regression model for these parameters showed strong predictive accuracy (AUC = 0.855, 95% CI 0.78–0.93). Importantly, the SA phase, rather than total asthma duration, was the critical factor, with each additional year reducing the odds of remission by ~10%. Conclusion: Clinical remission is a realistic goal in severe asthma, and early initiation of biologic therapy is vital for improving remission rates and long-term outcomes. Full article

Background and Objectives: Patients with type 2 diabetes mellitus (T2DM) are at a heightened risk of adverse outcomes from Coronavirus Disease 2019 (COVID-19). However, the influence of glycemic control on systemic inflammation and clinical severity remains incompletely understood. This study aimed to compare inflammatory markers, composite severity scores, and clinical outcomes between T2DM patients with COVID-19 who had well-controlled diabetes (hemoglobin A1c < 7%) versus those with poorly controlled diabetes (hemoglobin A1c ≥ 7%). Methods: We retrospectively reviewed 181 adult patients with T2DM and severe COVID-19 admitted to a tertiary hospital between January 2022 and December 2023. Patients were divided into two groups: well-controlled (n = 117) and poorly controlled (n = 64) T2DM. Baseline demographics, comorbidities, and laboratory parameters (C-reactive protein, interleukin-6, ferritin, neutrophil and lymphocyte counts, platelets, and calculated indices such as the neutrophil-to-lymphocyte ratio [NLR] and systemic immune-inflammation index [SII]) were collected. Composite severity scores (APACHE II, CURB-65, and NEWS) and clinical outcomes (ICU admission, mechanical ventilation, mortality, and length of stay) were compared. Statistical tests used included Student’s t-test or the Mann–Whitney U for continuous variables and chi-square for categorical variables, with p < 0.05 deemed significant. Results: The two groups did not differ significantly in age or duration of diabetes (p = 0.40 and p = 0.75, respectively). Patients with poorly controlled T2DM exhibited higher inflammatory markers (mean CRP of 93.4 mg/L vs. 78.6 mg/L, p = 0.002; IL-6 of 64.2 pg/mL vs. 52.8 pg/mL, p = 0.004) and elevated severity scores (APACHE II of 16.8 vs. 14.1, p = 0.001). Poor glycemic control was associated with higher ICU admissions (39.1% vs. 22.2%, p = 0.02) and mortality (14.1% vs. 6.0%, p = 0.05). Conclusions: In T2DM patients hospitalized with COVID-19, poor glycemic control correlates with heightened inflammatory responses, worse composite severity scores, and increased rates of unfavorable outcomes. These findings underscore the necessity of stringent glucose management to mitigate inflammation and improve prognoses in this vulnerable patient population. Full article

Background: Multiple myeloma (MM) is a hematological malignancy originating from the plasma cells present in the bone marrow. Despite significant therapeutic advancements, relapse and drug resistance remain major clinical challenges, highlighting the urgent need for novel therapeutic targets. Methods: To identify potential druggable genes associated with MM, we performed Mendelian randomization (MR) analysis. Causal candidates were further validated using a single-tissue transcriptome-wide association study (TWAS), and colocalization analysis was conducted to assess shared genetic signals between gene expression and disease risk. Potential off-target effects were assessed through an MR phenome-wide association study (MR-PheWAS). Additionally, molecular docking and functional assays were used to evaluate candidate drug efficacy. Results: The MR analysis identified nine druggable genes (FDR < 0.05), among which Orosomucoid 1 (ORM1) and Oviductal Glycoprotein 1 (OVGP1) were supported by both TWAS and colocalization evidence (PPH4 > 0.75). Experimental validation demonstrated the significant downregulation of ORM1 and OVGP1 in MM cells (p < 0.05). Pregnenolone and irinotecan, identified as agonists of ORM1 and OVGP1, respectively, significantly inhibited MM cell viability, while upregulating their expression (p < 0.05). Conclusions: Our study highlights ORM1 and OVGP1 as novel therapeutic targets for MM. The efficacy of pregnenolone and irinotecan in suppressing MM cell growth suggests their potential for clinical application. These findings provide insights into MM pathogenesis and offer a promising strategy for overcoming drug resistance. Full article

Background: Polycystin 1 (PC1) and polycystin 2 (PC2) proteins are members of the transient receptor potential (TRP) channels family and are encoded from PKD1 and PKD2 genes, respectively. Until recently, the role of PKD1 and PKD2 has been associated with the pathogenesis of the kidney since mutations in these genes cause autosomal dominant polycystic kidney disease (ADPKD). Recent data implicates polycystins in the pathogenesis of solid tumors. In this aspect, the expression of PKD1 and PKD2 in human astrocytomas is largely unknown. The aim of the present research study was to investigate the expression of PKD1 and PKD2 in astrocytic tumors and correlate it with clinicopathological characteristics such as the grade of malignancy, age, and gender of the patients. Methods: A total of 70 cases—corresponding to 8 grade II (diffuse fibrillary astrocytomas), 12 grade III (anaplastic astrocytomas), and 50 grade IV (glioblastomas multiforme)—were examined. The mRNA expression levels of PKD1 and PKD2 were determined through molecular qRT-PCR analysis using the relative quantification ΔΔCt method and the expression of PC1 and PC2 was detected through immunohistochemistry using the semi-quantitative H-score system. Results: Increased levels of PKD1 and PKD2 in astrocytomas were found compared with that of a normal brain (p < 0.05). Glioblastomas demonstrated the greatest increase in PKD1 and PKD2 expression compared to other grades of malignancy (p < 0.05). The same pattern of expression showed PC1 and PC2 proteins. A significant correlation between PKD1 and PKD2 as well as PC1 and PC2 expressions was found (p < 0.05). Although no association was detected between PC1 or PC2 and Ki67 expression (p > 0.05), a significant correlation between PC1 and p53 immunoexpressions, in grade III and between PC2 and p53 immunoexpressions, in grade II astrocytomas (p < 0.01) has emerged. PC1 expression was correlated with age of the patients (p < 0.05). PKD1 and PKD2 expression were negatively correlated with the prognosis of glioma patients. Conclusions: The results of this study indicate the potential involvement of polycystins in the pathogenesis of astrocytomas. However, further research is required to fully understand the mechanisms that these molecules are implicated. Full article

Objectives: Pancreatic cancer remains a therapeutic challenge due to its immunosuppressive microenvironment and treatment resistance. This study aimed to develop a novel recombinant oncolytic vaccinia virus (VVL-GL7) co-expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-7 (IL-7), designed to enhance anti-tumor immunity and synergize with immune checkpoint inhibitors. Methods: VVL-GL7 was constructed through CRISPR/Cas9-mediated knockout of TK and A49 genes, combined with the simultaneous insertion of dual cytokine-encoding cassettes. Anti-tumor efficacy was evaluated in vitro and in vivo using C57BL/6 mouse and Syrian hamster pancreatic cancer models. Comprehensive immune profiling evaluated CD8⁺ T-cell and macrophage infiltration dynamics while simultaneously assessing memory T-cell differentiation patterns using flow cytometry. Preclinical combination studies of VVL-GL7 and the PD-1 immune checkpoint inhibitor were systematically evaluated in a syngeneic pancreatic cancer model. Results: VVL-GL7 exhibited potent oncolytic activity, inducing significant tumor regression in both preclinical models. VVL-GL7 therapy significantly augmented CD8⁺ T-cell and macrophage infiltration within the tumor microenvironment, while concomitantly driving memory T-cell differentiation. The synergistic effects of VVL-GL7 and the PD-1 blockade further improved therapeutic outcomes, resulting in significantly higher tumor remission rates compared to monotherapy and achieving complete tumor regression in pancreatic cancer models. Conclusions: VVL-GL7 reprograms the immunosuppressive tumor microenvironment and synergizes with anti-PD-1 antibodies to overcome resistance in pancreatic cancer. Full article

Background: Our previous study demonstrated that miR-140-3p induced osteocalcin expression in osteoblastic MC3T3-E1 cells. In this study, we investigated the direct effects of miR-140-3p on bone turnover in senescence-accelerated mice. Methods: In order to evaluate the effects of miR-140-3p, we formulated lipid nanoparticles (LNPs) containing miR-140-3p (100 μg/mL), with or without flotillin-2 (Flo2), a microvesicle marker excreted by osteoblasts. LNP was administered into the right tibia of the P6 strain of senescence-accelerated mice (SAMP6). Four-week-old SAMP6 males were divided into three groups: control, LNP, and LNP + Flo2. LNPs were administered five times, once every three days. No gait abnormalities were observed in any group. Two days after the last administration of LNPs, blood and urine samples were collected to measure bone turnover markers and blood chemistry and to perform urinalysis. Bone histomorphometry was performed on the left femur, contralateral to the administration site. The pancreas was removed for insulin staining of the Langerhans islets. Results: The LNP + Flo2 group showed greater bone volume, trabecular thickness, and osteoid thickness in bone histomorphometry. Carboxylated osteocalcin, a bone formation marker, was also higher in the LNP + Flo2 group, indicating that LNP + Flo2 activated osteoblastic function. Insulin levels in the islets of Langerhans did not differ across the groups, consistent with under-carboxylated osteocalcin levels. Conclusions: LNP + Flo2 effectively improved bone metabolism. Full article

Traumatic brain injury (TBI) has been linked to the development of neurodegenerative diseases, particularly Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). This review critically assesses the relationship between TBI and cerebral amyloid angiopathy (CAA), highlighting the complexities of diagnosing CAA in the context of prior head trauma. While TBI has been shown to facilitate the accumulation of amyloid plaques and tau pathology, the interplay between neurodegenerative processes and vascular contributions remains underexplored. Epidemiological studies indicate that TBI increases the risk of various dementias, not solely AD, emphasizing the need for a comprehensive understanding of TBI-related neurodegeneration as a polypathological condition. This review further delineates the mechanisms by which TBI can lead to CAA, particularly focusing on the vascular changes that occur post-injury. It discusses the challenges associated with diagnosing CAA after TBI, particularly due to the overlapping symptoms and pathologies that complicate clinical evaluations. Notably, this review includes a clinical case that exemplifies the diagnostic challenges posed by TBI in patients with subsequent cognitive decline and vascular pathology. By synthesizing current research on TBI, CAA, and associated neurodegenerative conditions, this review aims to foster a more nuanced understanding of how these conditions interact and contribute to long-term cognitive outcomes. The findings underscore the importance of developing standardized diagnostic criteria and imaging techniques to better elucidate the relationship between TBI and vascular pathology, which could enhance clinical interventions and inform therapeutic strategies for affected individuals. Full article

Background/Objectives: Despite its heterogeneity and diagnostic challenges, acute myeloid leukemia (AML) originates from stem cell transformation and alterations in the hematopoietic niche (HN) could be related to leukemic transformation. Therefore, the aim of this study was to evaluate the protein profile of HN from AML patients and compare it with the profile of healthy donors (HDs). Methods: A proteomic analysis was conducted to identify differentially expressed (DE) proteins in BM plasma from AML patients and HD. In silico analysis was performed to identify biological processes and signaling pathways involved. Additionally, ELISA confirmed the expression of the DE protein of interest in BM plasma samples. Results: Proteomic analysis revealed alterations in the plasma profiles of AML patients and 36 DE proteins were found. Among then, we highlight C8G, CFB, SAA1, SERPINA3 and SERPINC1, which are related to inflammatory response process. Thus, considering the role of the secreted protein SAA1 in the inflammatory context and that it is described as a potential biomarker in several tumors, we selected SAA1 for ELISA confirmation. The results corroborated our findings, indicating that increased expression of SAA1 could be related to AML. Our results also revealed that SAA1 can stimulate immune signaling through NF-kappa-B activation. Conclusions: These findings position SAA1 as a promising biomarker for AML diagnosis, offering a potential tool for more accurate identification of the disease. Nevertheless, further studies are needed to understand the relationship of SAA1 with the leukemic transformation process in AML and its potential clinical use. Full article

Background: Besides conventional norms that recognize synovial fluid (SF) as a joint lubricant, nutritional channel, and a diagnostic tool in knee osteoarthritis (kOA), based on the authors previous studies, this study aims to define functional role of SF in kOA. Methods: U937, a monocytic, human myeloid cell line, was induced with progressive grades of kOA SF, and the induction response was assessed on various pro-inflammatory parameters. This ‘SF challenge test model’ was further extended to determine the impact of SF on U937 differentiation using macrophage-specific markers and associated transcription factor genes. Mitochondrial membrane potential changes in SF-treated cells were evaluated with fluorescent JC-1 probe. Results: a significant increase in nitric oxide, matrix metalloproteinase (MMP) 1, 13, and vascular endothelial growth factor (VEGF)-1 was noted in the induced cells. A marked increase was seen in CD68, CD86, and the transcription factors –activator protein (AP)-1, interferon regulatory factor (IRF)-1, and signal transducer and activator of transcription (STAT)-6 in the SF-treated cells indicating active monocytes to macrophage differentiation. Reduced mitochondrial membrane potential was reflected by a reduced red-to-green ratio in JC-1 staining. Conclusions: these results underline the active role of OA SF in stimulating and maintaining inflammation in joint cells, fostering monocyte differentiation into pro-inflammatory macrophages. The decline in the membrane potential suggestive of additional inflammatory pathway in OA via the release of pro-apoptotic factors and damaged associated molecular patterns (DAMPs) within the cells. Overall, biochemical modulation of SF warrants a potential approach to intervene inflammatory cascade in OA and mitigate its progression. Full article

Background: Organoids are a valuable model for studying hereditary diseases such as cystic fibrosis (CF). Recombinant adenoviral (rAdV) and adeno-associated viral (rAAV) vectors are promising tools for CF gene therapy and genome editing. Objective: This study aims to determine the most efficient viral vector (rAdV5, rAAV serotypes 5, 6 and 9) and transduction protocol for delivering transgenes to lung organoids (LOs), providing a foundation for future CF gene therapy development. Methods: Three transduction protocols were used taking into account the specificities of LOs’ cultivation in specific matrices, both with and without organoid extraction from the matrix. This work was carried out on organoids from a healthy donor (LOs-WT) and on a patient with cystic fibrosis (LOs-CF). Results: High transduction efficiency was observed with rAdV5 (30% cells), rAAV6 (>80% cells), and rAAV9 (>40% cells). rAdV5 and rAAV9 transduced basal and secretory cells with >90% efficiency. For rAAV9, Protocol 1 (without extraction of organoids from the matrix) showed lower transduction efficiency (33% for LOs-WT, 9% for LOs-CF), significantly lower than that of Protocols 2 (60% for LOs-WT, 59% for LOs-CF) and 3 (46% for LOs-WT, 35% for LOs-CF) with organoid extraction from the matrix (p < 0.005). Conclusions: rAdV5 and rAAV9 are the most promising vectors for the delivery of transgenes to basal and secretory cells in a lung organoid model, providing a solid foundation for CF gene therapy development. Full article

Background: Ovarian cancer (OC) is a heterogeneous malignancy associated with a poor prognosis, necessitating robust biomarkers for risk stratification and therapy optimization. Cellular senescence-related genes (CSGs) are emerging as pivotal regulators of tumorigenesis and immune modulation, yet their prognostic and therapeutic implications in OC remain underexplored. Methods: We integrated RNA-sequencing data from TCGA-OV (n = 376), GTEx (n = 88), and GSE26712 (n = 185) to identify differentially expressed CSGs (DE-CSGs). Consensus clustering, Cox regression, LASSO-penalized modeling, and immune infiltration analyses were employed to define molecular subtypes, construct a prognostic risk score, and characterize tumor microenvironment (TME) dynamics. Drug sensitivity was evaluated using the Genomics of Drug Sensitivity in Cancer (GDSC)-derived chemotherapeutic response profiles. Results: Among 265 DE-CSGs, 31 were prognostic in OC, with frequent copy number variations (CNVs) in genes such as STAT1, FOXO1, and CCND1. Consensus clustering revealed two subtypes (C1/C2): C2 exhibited immune-rich TME, elevated checkpoint expression (PD-L1, CTLA4), and poorer survival. A 19-gene risk model stratified patients into high-/low-risk groups, validated in GSE26712 (AUC: 0.586–0.713). High-risk patients showed lower tumor mutation burden (TMB), immune dysfunction, and resistance to Docetaxel/Olaparib. Six hub genes (HMGB3, MITF, CKAP2, ME1, CTSD, STAT1) were independently predictive of survival. Conclusions: This study establishes CSGs as critical determinants of OC prognosis and immune evasion. The molecular subtypes and risk model provide actionable insights for personalized therapy, while identified therapeutic vulnerabilities highlight opportunities to overcome chemoresistance through senescence-targeted strategies. Full article

Background: Over thirty years of basic research has demonstrated that the deuterium-to-hydrogen ratio plays a pivotal role in regulating metabolism and cell growth via a sub-molecular regulatory system that orchestrates the intricate complexity of life in eukaryotic organisms. Deuterium depletion, achieved through deuterium-depleted water (DDW), has shown anticancer effects in vitro, in vivo, and in Phase 2 prospective and retrospective clinical studies. Methods: In this population-based observational study, 2649 cancer patients undergoing conventional therapy and consuming DDW were included between October 1992 and October 2024. With various cancer types and stages and conventional therapies received, they are representing a broad spectrum of the Hungarian cancer population. Survival was selected as the primary endpoint, and the median survival time (MST) of these patients and various subgroups was calculated and compared to the overall Hungarian cancer population’s MST of 2.4 years. Results: For the entire study population, MST from diagnosis was 12.4 years (95% CI: 9.8–14.9), and from the initiation of DDW treatment, 7.6 years (95% CI: 5.9–9.3). Conclusions: Utilizing DDW enables targeted intervention in the sub-molecular regulatory system, paving the way for innovative therapeutic applications and a more profound understanding of cellular processes. Integrating deuterium depletion into conventional cancer therapies has the potential to significantly enhance survival rates and reduce cancer-related mortality by 75–80%. Full article