Tumor Suppressor Research Articles

Switching on the evolutionary potential of pancreatic cancer: the tumor suppressor functions of PBRM1

Switching on the evolutionary potential of pancreatic cancer: the tumor suppressor functions of PBRM1

Effect of cell proliferation pathway on accessibility to targeted therapeutics in the spectrum of co-occurring prognostic cellular pathways in pan-cancers.

e15092 Background: Cellular pathways play a crucial role in prognosis and development of targeted therapies by impacting molecular mechanisms underlying disease progression. Targeted therapies can significantly reduce side effects while offering the potential to overcome challenges like drug resistance. This study aims to investigate prognostic cellular pathways that may be promising in guiding drug interactions pan-cancers. Methods: A cohort of 82 pan-cancer patients (Breast, Colorectal, Endometrium, Gall Bladder, Gastric, HNC, Lung, Melanoma, Ovary, Pancreas, Prostate, Urothelium) were retrospectively analyzed to understand the distribution of cellular pathways. Next Generation Sequencing (NGS) test was performed using OncoIndx Assay. Results: A total of 99 genomic alterations distributed across cellular pathways including proliferation, progression, dsDNA Repair, mismatch repair (MMR), tumor suppression and cell signaling were detected. Cell proliferation pathway alterations constituted the highest frequency with 43 mutations in 34.14% of patients while 31 alterations in tumor suppressor genes were identified in 34.14% patients. MMR and cell signaling pathways included a minor 2 and 1 alterations. Crucial pathways were also identified to co-occur with cell proliferation including tumor suppression (n = 13/28), cell progression (n = 2/28), dsDNA repair (n = 3/28), and MMR pathways (n = 2/28). From this group, 1 patient had recently undergone surgery showing no e/o recurrence or residual disease and the other patient was started with oral chemotherapy (capecitabine). Interestingly, both patients showed co-occurring tumor suppression pathway alterations. Conclusions: Cell proliferation pathway alterations, by presenting themselves as co-occurring with tumor suppression, cell progression, dsDNA repair and MMR pathway, open newer targets for multiple treatment lines.

Potential targets for synergistic bipolar irreversible electroporation in tumor suppression through transcriptomics and proteomics analysis.

Potential targets for synergistic bipolar irreversible electroporation in tumor suppression through transcriptomics and proteomics analysis.

The Protective Role of miR-125b in Hepatocellular Carcinoma: Unraveling Tumor-Suppressive Mechanisms

MicroRNAs (miRNAs) have emerged as crucial regulators of gene expression, playing pivotal roles in various biological processes, including cancer development and progression. Among them, miR-125b has garnered significant attention due to its multifaceted functional roles in human hepatocellular carcinoma (HCC). Extensive research has revealed that miR-125b plays a dual role in HCC, acting as both a tumor suppressor and an oncogene, depending on the context. As a tumor suppressor, miR-125b inhibits HCC by targeting key oncogenic pathways and genes involved in cell proliferation, migration, invasion, and angiogenesis. Its downregulation in HCC is frequently observed and correlates with aggressive tumor characteristics and poor prognosis. Conversely, miR-125b can also function as an oncogene in specific HCC subtypes or under certain conditions. It has been shown to promote HCC growth, metastasis, and therapeutic resistance by targeting tumor suppressor genes, modulating the epithelial-mesenchymal transition (EMT) process, and enhancing cancer stem cell-like properties. The upregulation of miR-125b in HCC has been associated with advanced disease stages and unfavorable clinical outcomes. Furthermore, a complex network of regulatory mechanisms influences the dysregulation of miR-125b expression in HCC. Understanding these regulatory mechanisms is crucial for deciphering the precise functional roles of miR-125b in HCC and exploring its potential as a diagnostic biomarker or therapeutic target. In the current review study, we comprehensively elucidated the diverse functional roles of miR-125b in HCC, providing a comprehensive overview of its regulatory mechanisms and impact on key cellular processes involved in HCC progression.

Cellular proliferation and tumor suppression pathways as potential targets in clinically aggressive sarcomas.

e23551 Background: Sarcomas are rare, heterogeneous, and aggressive malignancies with poor prognosis, driven by dysregulated proliferation pathways (e.g., CDK4/6, c-Myc) and impaired tumor suppression mechanisms (e.g., CDKN2A/p16INK4a-RB, p14ARF-MDM2-p53). These genetic alterations result in uncontrolled growth, metastasis, and therapy resistance. Emerging therapies targeting these pathways, such as CDK4/6 inhibitors and MDM2 antagonists, show promise. Furthermore, genomic testing can provide insights into mesenchymal stem cell-derived sarcomagenesis and oncogenic microenvironmental interactions providing new opportunities for precision-based treatments. This study investigates molecular pathways in aggressive sarcomas which could assist in expanding targeted treatment options beyond the current common genetic fusions. Methods: Retrospectively, we investigated the comprehensive genomic profiling of 10 sarcoma patients including subtypes leiomyosarcoma(n=2), ewing sarcoma(n=1), metastatic angiosarcoma(n=2), extraskeletal myxoid chondrosarcoma(n=1), pleomorphic liposarcoma(n=1), retroperitoneal leiomyosarcoma(n=1), soft tissue sarcoma(n=1) and differentiated spindle cell sarcoma(n=1) at different disease stages including progressive, metastatic, and recurrent disease types. Next Generation Sequencing (NGS) test was performed using OncoIndx Assay (Shafi et al., 2024). Results: The study cohort comprised 10 sarcoma patients, including males (n=6) and females (n=4). Disease stages included progressive (n=4), metastatic (n=3), and recurrent (n=3), as identified through PET scans and histopathological examination (HPE). Recent therapeutic regimen predominantly included chemotherapy (Eribulin, Palliative chemo, Trabectedin, Gem + Docetaxel), combined therapy (Paclitaxel + Pembro, Pazopanib + DCT), and surgery. Primary genomic findings highlighted the impairment of two critical pathways including cell proliferation (n=3/10) and tumor suppression (n=4/10). Further, no genomic alteration was detected in three patients despite aggressive disease as per PET/HPE findings. In addition, genomic findings from three patients also exhibited a high tumor mutation burden (TMB) thereby expanding their possibilities to immunotherapy. Conclusions: This study highlights the utility of comprehensive genomic profiling in broadening the scope of treatment by highlighting the exact drivers for and disease aggressiveness in sarcomas. The presence of genomic alterations in cell proliferation and tumor suppression pathways could also be early indicators of disease aggressiveness if closely monitored. With only a few selected fusions currently crucial in sarcomas, this study extends the molecular repertoire for practice. Also, additional analysis like RNA sequencing might be more beneficial in such scenarios.

Computational identification and experimental characterization of an aurora kinase inhibitor.

Computational identification and experimental characterization of an aurora kinase inhibitor.

Enhancing glioblastoma therapy with a recombinant Newcastle disease virus harboring the PTEN gene.

e15185 Background: Glioblastoma (GBM), a highly aggressive brain tumor, is challenging to treat due to its resistance to conventional therapies and the restrictive nature of the blood-brain barrier (BBB). Loss or dysfunction of the tumor suppressor PTEN, prevalent in approximately 40% of GBM cases, contributes to tumor progression via activation of the PI3K/AKT/mTOR pathway. Newcastle disease virus (NDV), an intrinsic oncolytic virus, demonstrates the unique ability to penetrate the BBB and selectively target tumor cells. Methods: A recombinant NDV encoding the human PTEN gene (rNDV-PTEN) was developed to enhance therapeutic efficacy. PTEN was strategically inserted between the NP and P genes of the NDV genome for optimal expression. In vitro and in vivo studies evaluated rNDV-PTEN’s capacity to restore PTEN expression, inhibit tumor growth, and cross the BBB. Human GBM cell lines (e.g., U87-MG) and an orthotopic mouse model were used for functional analyses, including proliferation, migration, apoptosis, and tumor burden assessments. Results: rNDV-PTEN successfully delivered the PTEN gene to GBM cells, resulting in significant PTEN protein expression and restoration of its tumor suppressor function. This restoration inhibited tumor growth by suppressing the PI3K/AKT/mTOR pathway. In vitro, rNDV-PTEN treatment reduced GBM cell proliferation and migration while inducing apoptosis. In vivo, intravenous administration of rNDV-PTEN demonstrated efficient BBB penetration, leading to localized PTEN delivery, significant tumor size reduction, and improved survival in GBM-bearing mice. MRI and histopathological evaluations confirmed these effects. Notably, rNDV-PTEN exhibited specificity for tumor cells, leaving normal astrocytes unaffected. Conclusions: This study highlights the potential of rNDV as a delivery vehicle capable of crossing the BBB and selectively targeting GBM. The combination of NDV’s intrinsic oncolytic properties and PTEN’s tumor-suppressive functions offers a promising therapeutic strategy for treating PTEN-deficient GBM.

Advancements of anticancer agents by targeting the Hippo signalling pathway: biological activity, selectivity, docking analysis, and structure-activity relationship.

The Hippo signalling pathway is prominent andgoverns cell proliferation and stem cell activity, acting as a growth regulator and tumour suppressor. Defects in Hippo signalling and hyperactivation of its downstream effector's Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play roles in cancer development, implying that pharmacological inhibition of YAP and TAZ activity could be an effective cancer treatment strategy. Conversely, YAP and TAZ can also have beneficial effects in promoting tissue repair and regeneration following damage, therefore their activation may be therapeutically effective in certain instances. Recently, a complex network of intracellular and extracellular signalling mechanisms that affect YAP and TAZ activity has been uncovered. The YAP/TAZ-TEAD interaction leads to tumour development and the protein structure of YAP/TAZ-TEAD includes three interfaces and one hydrophobic pocket. There are clinical and preclinical trial drugs available to inhibit the hippo signalling pathway, but these drugs have moderate to severe side effects, so researchers are in search of novel, potent, and selective hippo signalling pathway inhibitors. In this review, we have discussed the hippo pathway in detail, including its structure, activation, and role in cancer. We have also provided the various inhibitors under clinical and preclinical trials, and advancement of small molecules their detailed docking analysis, structure-activity relationship, and biological activity. We anticipate that the current study will be a helpful resource for researchers.

P14ARF interacts with γ-H2AX and is involved in the DNA damage response.

p14ARF interacts with γ-H2AX and is involved in the DNA damage response.

The CNC-family transcription factor NRF3: A crucial therapeutic target for cancer treatment.

The CNC-family transcription factor NRF3: A crucial therapeutic target for cancer treatment.

KEAP1 mutated renal cell carcinoma (RCC): Characterization of an emerging molecularly defined RCC subtype.

4547 Background: KEAP1 is a tumor suppressor and negative regulator of the NRF2 pathway, and inactivating KEAP1 mutations (mts) have been reported in patients (pts) with RCC with similar morphology to fumarate hydratase (FH)-deficient RCC (FH-RCC). In FH-RCCs, the NRF2 pathway is activated through fumarate-led inactivation of KEAP1, and we hypothesized that KEAP1 mts are drivers in RCC, similar to FH mts in FH-RCC. We sought to characterize RCC with KEAP1 mts as a separate RCC subtype and compare to FH-RCC and clear cell (cc)RCC. Methods: Among consecutive pts with RCC consented to tumor-normal DNA sequencing via MSK-IMPACT (NCT01775072), we identified patients with germline or somatic mutations in KEAP1 or FH and no other known driver mts (ie VHL, MET, TFE3 alterations), and categorized these as “KEAP1-RCC” or “FH-RCC.” Clinicopathologic characteristics and outcomes were analyzed and compared to pts with FH-RCC and a previously annotated subset ccRCC (n=162). Immunohistochemical (IHC) staining for NQO1, marker of NRF2 activation, was performed. Time on systemic treatment and overall survival (OS) from time of sequencing were assessed. Results: Among 928 pts with RCC, 13 (1.4%) and 26 (2.8%) had RCCs with KEAP1 and FH mts, respectively. KEAP1 and FH mts were mutually exclusive. Median age was younger in FH-RCC (47 vs 63) (Table). When compared to ccRCC, OS was significantly worse for FH-RCC (HR 2.4, 95% CI 1.4-4.1; p=0.02) but not for KEAP1-RCC (HR 1.07, 95% CI 0.29-3.0; p=0.89). All KEAP1-RCC and FH-RCC were histologically classified as non-cc except one KEAP1-RCC that had 3p loss and no VHL mt. All available KEAP1 and FH-RCC were NQO1+ on IHC; control ccRCC were all negative. In the KEAP1-RCC cohort, we identified a female with an unclassified RCC and a germline KEAP1 truncating variant; RCC tumor had a second KEAP1 somatic mutation and was NQO1+ on IHC. The germline variant cosegregated to a sister with lung cancer (IHC NQO1+) and anal cancer. Conclusions: RCC with KEAP1 mts and no other genomic drivers are primarily non-cc with papillary features, have functional evidence of NRF2 activation, and although high-grade may have better outcomes than FH-RCC. KEAP1-RCC appears to be an emerging molecularly defined RCC subtype with clinical behavior similar to FH-RCC, likely as a result of converging on NRF2 pathway activation. Clinical characteristics. KEAP1-RCC (n=13) FH-RCC (n=26) ccRCC (n=162) Age (range) 63 (26-71) 47 (20-74) 56 (24-78) Male 8 (62%) 17 (65%) 125 (77%) Tumor size (cm), median (IQR) 5.6 (5.1, 11.0) 8.0 (5.0, 14.0) 8.2 (6.0, 10.5) Histology FH-deficient 0 13 (50%) 0 Papillary features 8 (62%) 4 (15%) 0 Unclassified 1 (8%) 8 (31%) 0 ccRCC 1 (8%) 0 162 (100%) Other/Unknown 3 (23%) 1 (4%) 0 Tumor grade, high 13 (100%) 26 (100%) 134 (83%) Metastatic 9 (69%) 25 (96%) 150 (93%)

Identification of KANK1 as a tumor suppressor gene in pancreatic ductal adenocarcinoma.

Identification of KANK1 as a tumor suppressor gene in pancreatic ductal adenocarcinoma.

Discovery and biochemical characterization of the D-aspartyl endopeptidase activity of the serine protease LACTB.

Nonenzymatic D-isomerization of aspartic acid in proteins has been observed in lesions associated with age-related diseases, including cataracts and Alzheimer's disease. Given that D-isomerization of Asp disrupts the physiological conformation of proteins, it has been postulated that D-isomerization of Asp in proteins is a key factor in the pathogenesis of age-related diseases. D-Aspartyl endopeptidase (DAEP) activity, which cleaves proteins at the carboxy terminus of D-Asp and potentially induces degradation of abnormal proteins with D-isomerized Asp, has been observed in mitochondrial fractions of mammalian tissues. However, the specific proteins responsible for mammalian DAEP activity remain unknown. In this study, we identified mitochondrial serine β-lactamase-like protein (LACTB) as the first mammalian protein with DAEP activity by structural comparison with paenidase, a bacterial DAEP. LACTB exhibited DAEP activity similar to paenidase in an in vitro assay. In addition, LACTB cleaved a 10-residue peptide derived from amyloid β1-10 containing D-Asp at position 7, which was also observed with mammalian DAEP. LACTB has previously been characterized as a tumor suppressor and as a protein whose increased expression is associated with an increased risk of Alzheimer's disease. Therefore, our findings suggest that disruption of the proteostasis of D-Asp-containing proteins may underlie the pathogenesis of these diseases.

Assessment of plasma ctDNA mutational profile and heterogeneity in renal cell carcinoma patients.

e14544 Background: Renal cell carcinoma (RCC) is a common form of kidney cancer that presents significant challenges in both diagnosis and treatment. Despite advancements in therapy, approximately 30% of patients experience recurrence, underscoring the pressing need for improved disease management strategies. Incorporating genomic insights into RCC care offers a promising pathway for personalized treatment and more accurate disease prognostication. In addition to tissue biopsy, liquid biopsy using circulating tumor DNA (ctDNA) has emerged as a viable alternative, enabling personalized treatment decisions, longitudinal monitoring for early relapse detection, and treatment resistance. We compared comprehensive genomic profiling (CGP) using tissue DNA and ctDNA from RCC patients to explore their mutational landscape and enhance the standard of care. Methods: In this retrospective study, 30 patients (Pts) advanced RCC treated with standard of care underwent targeted hybrid-capture based genomic profiling using OncoIndx (1080 genes) CGP platform and OncoMonitor (108 gene) tumor panel either on tumor tissue or plasma ctDNA. Enriched libraries were sequenced (average depth: 5500 X for ctDNA; 2500 X for tissue DNA) in a pair end fashion (150 x2) on Illumina Nextseq 2000. Raw sequencing reads were converted into BAM files and processed for variant calling using a proprietary bioinformatics pipeline iCare. Variants were called according to ClinVar, ACMG and AMP databases. Results: Of the 30 samples sequenced, 24 (75%) were blood-derived, while 6 (25%) were tissue-derived (tDNA). Pathogenic mutations were detected in 23 samples (77%). Among these, the most frequent variants were loss-of-function (LOF) VHL mutations and TP53 mutations (23%), followed by MSH6 (16.6%) and SMAD4 (13%). A significant subset of samples (29.6%) exhibited pathogenic gain of function mutations in KRAS and BRAF (16.6%), along with variants in the PIK3CA pathway ( PIK3CA , PTEN , and AKT ) (13%), suggesting oncogenic signaling as a key driver. About 80 % samples had tumor suppressor (TS) mutations in at least one homologous recombination repair (HRR) pathway gene. Pathogenic variants in CHEK2 , PALB2 , and FANCA/FANCC were associated with high HRD scores (P = 0.03, Odds Ratio: 8.8). Interestingly, gain of function TP53 mutations and genomic instability (high HRD or TMB scores) was prevalent in metastatic tumors. ctDNA demonstrated a more diverse mutation profile compared to tissue DNA, reflecting broader tumor heterogeneity. Conclusions: The potential of ctDNA-based genomic profiling is of higher clinical implications for uncovering the mutational landscape and addressing the challenges of tumor heterogeneity in RCC. The key TS variants along with dysregulated KRAS and PIK3CA pathway mutations were enriched in ctDNA compared to tDNA. ctDNA offers a promising non-invasive approach for improved disease management in RCC.

Exploring the fibronectin/p21 (CDKN1A) functional axis in breast cancer as a marker of an aggressive disease subgroup.

e12557 Background: Breast cancer is a highly heterogeneous disease concerning both cancer cells and the tumor microenvironment (TME). Fibronectin ( FN1 ) is a protein identified as an extracellular matrix (ECM) component in breast cancer TME and its expression correlates with the epithelial to mesenchymal transition (EMT) and the triple-negative phenotype. Cyclin-dependent kinase inhibitor 1A ( CDKN1A/p21 ) is a multifaced protein with roles in cell cycle regulation, DNA damage response, and cellular senescence induction, that can function either as an oncogene or as a tumor suppressor. To study a possible interaction pathway between cancer cells and the TME we assessed p21 expression in tumor cells and FN1, in conjunction to clinicopathological parameters. Methods: We employed Immunohistochemistry (IHC) for p21 (CDKN1A) and Fibronectin (FN1) protein expression on FFPE breast cancer samples and the Breast Invasive Carcinoma, TCGA, Firehose legacy data set through cBioPortal for analysis of patient clinicopathological parameters. Correlations were tested through the SPSS package and gene set enrichment analysis was done through g.Profiler online tool. Results: Here, by p21 and Fibronectin IHC in breast cancer FFPE tissue samples, we identified a statistically significant positive correlation (p=0.02) between p21 nuclear expression and a complex Fibronectin expression pattern in both cancer cells and TME. Next, we confirmed a positive correlation of p21 and FN1 through analysis of the Breast Invasive Carcinoma, TCGA data set for both proteins, in both ER-positive (p=1.41e -24 ) and ER-negative populations (p=3.73e -7 ). In addition, we identified in the same data set a patient subgroup overexpressing simultaneously both proteins (p21 high, FN1 high) with statistically significant worse overall survival (OS) (p=0.0193, HR 0.479). According to gene set enrichment analysis of the p21/FN1 double positive subgroup of patients we identified a gene signatures that encompassed gene ontology terms related to system development (p=1.755x10 -65 ), extracellular matrix organization (p=1.315x10 -59 ), cell adhesion (p=4.012x10 -50 ) and cell migration (p=7.471x10 -34 ). Finally, in order to test a possible link between DNA damage-induced p21 expression and the simultaneous upregulation of fibronectin, we subjected breast cancer cell lines to Etoposide treatment in vitro and tested through immunofluorescence for protein expression. Concurrent upregulation of p21 and fibronectin in vitro by cancer cells, further supported the notion of a complex interplay between tumor cells and TME in breast cancer. Conclusions: Collectively, our preliminary results indicate that ECM fibronectin deposition and cancer cell fibronectin expression in relation to p21 in breast cancer is a complex phenomenon, regulated by diverse molecular pathways, with a possible impact on disease outcomes.

MiR-326: Role and significance in brain cancers.

MiR-326: Role and significance in brain cancers.

Drug repurposing of 6-AZA-UTP and itraconazole reveals novel B3GALT5 inhibitors for pancreatic cancer.

Drug repurposing of 6-AZA-UTP and itraconazole reveals novel B3GALT5 inhibitors for pancreatic cancer.

ImNEO: High-accuracy neoantigen prediction through AI-based integrated analysis of multiple immunogenicity-related factors.

e14639 Background: Neoantigens have emerged as compelling targets for cancer vaccines, with early clinical trials confirming their safety and efficacy. Accurate prediction of neoantigens is critical for the successful development of personalized cancer vaccines. Here, we present imNEO, a highly accurate neoantigen prediction platform that integrates multiple immunogenicity-related factors. Methods: Experimentally validated human tumor neoantigens were collected. Previously reported immunogenicity-related factors, along with newly developed factors, were tested for their association with immunogenicity. Integrated machine learning models were constructed and evaluated using data from melanoma, lung cancer, and gastrointestinal cancers. To verify prediction accuracy, immunogenicity using IFN-γ ELISPOT assays, tumor growth inhibition, and antibody secretion using ELISA were assessed in a colon cancer mouse model. Results: A total of 30 factors, encompassing epitope properties, antigen processing and presentation, T-cell interaction, the tumor microenvironment, and the differential index between mutant and wild-type, were identified as being associated with the immunogenicity of neoantigens. Seven machine learning algorithms were integrated to construct the immunogenicity prediction model. Across multiple human cancer datasets, imNEO demonstrated up to a 15.6% increase in the area under the precision-recall curve compared to existing methods. Notably, positive predictive values for the top 10 and 20 ranked neoantigens were 85% and 70% on average, respectively. In immunogenicity tests, 19 out of 25 (76%) neoantigens identified from the MC38 colon cancer model induced strong IFN-γ secretion, confirming a high immunogenicity rate suitable for application in personalized cancer vaccines. In tumor growth inhibition and antibody secretion tests, neoantigen-treated groups exhibited significantly reduced tumor growth (p = 1.26E-05) and increased IgG antibody secretion, demonstrating that imNEO-predicted neoantigens possess the necessary characteristics for effective tumor suppression. Conclusions: imNEO significantly advances neoantigen prediction, integrating immunogenicity-related factors to achieve superior accuracy. Experimental validation confirmed high immunogenicity and tumor-suppressive effects, highlighting its potential for developing effective personalized cancer vaccines.

Network pharmacology analysis of phytochemicals in targeting cancer: A systems biology approach.

e15130 Background: The intricate nature of cancer necessitates an integrative approach to uncover novel therapeutic strategies. Phytochemicals derived from medicinal plants offer a rich source of bioactive compounds with potential anti-cancer properties. Methods: This study utilises a network pharmacology framework to investigate the molecular mechanisms and multi-target effects of key phytochemicals, including quercetin, berberine, resveratrol, epigallocatechin gallate, salvianolic acids, and ginsenosides, against cancer pathways. Using a curated database of cancer-related targets, we employed molecular docking, ADMET profiling, and pathway enrichment analysis to identify and validate critical interactions between these phytochemicals and oncogenic pathways. Results: Gene Ontology (GO) analysis revealed significant enrichment in biological processes such as apoptosis regulation, cell cycle modulation, and oxidative stress responses. KEGG pathway mapping highlighted pivotal pathways, including PI3K-Akt, MAPK, and p53 signaling, as central nodes in the network, underscoring their role in tumour suppression and proliferation control. Moreover, systems pharmacology tools demonstrated the interconnectedness of phytochemicals in modulating mitochondrial function, cellular metabolism, and immune response which are recognized hallmarks of cancer progression. Conclusions: Our findings suggest that the multi-target and pleiotropic actions of these compounds are instrumental in mitigating cancer's complex pathophysiology. By integrating in silico predictions with experimental validations, we provide a blueprint for developing phytochemical-based combinatory therapies tailored to specific cancer types. This study not only advances our understanding of plant-derived compounds in oncology but also emphasizes the potential of network pharmacology as a transformative approach in drug discovery. We propose that future research and clinical trials should explore the therapeutic efficacy of these phytochemicals as part of multi-target regimens to improve treatment outcomes.

Dipeptidyl peptidase 9 (DPP9) depletion from hepatocytes in experimental primary liver cancer.

Dipeptidyl peptidase 9 (DPP9) depletion from hepatocytes in experimental primary liver cancer.