Search Results (286)

Epigallocatechin-3-gallate (EGCG), the major bioactive polyphenol in green tea, has garnered significant attention for its potential anticancer properties. This review summarizes the current evidence from in vitro, in vivo, and clinical trials examining the effects of EGCG on lung cancer. EGCG exerts its anticancer effects through various mechanisms, including the inhibition of cell proliferation, induction of apoptosis, suppression of metastasis, and modulation of signalling pathways such as epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB). Additionally, EGCG has been shown to enhance the efficacy of conventional chemotherapeutic agents and mitigate drug resistance. However, challenges related to its bioavailability and metabolic stability remain. Ultimately, this review aims to provide a comprehensive overview of the effects of EGCG against lung cancer. Full article

Inflammatory bowel disease (IBD) is characterized by excessive oxidative stress, mitochondrial dysfunction, and persistent activation of pro-inflammatory signaling pathways. Danthron, a natural anthraquinone derivative from rhubarb, has been reported to possess anti-inflammatory and antioxidant properties, yet its regulatory mechanisms in intestinal inflammation remain unclear. In this study, we combined network pharmacology, transcriptomic profiling, cell-based assays, intestinal organoids, and a dextran sulfate sodium (DSS)-induced colitis model to determine the protective effects of Danthron against oxidative injury. Integrated target prediction and RNA-seq analysis identified EGFR–PI3K–AKT and Nrf2–HO-1 as key signaling axes modulated by Danthron. In macrophages and intestinal epithelial cells, Danthron markedly suppressed LPS- or H₂O₂-induced ROS accumulation, lipid peroxidation, and mitochondrial membrane potential collapse, while restoring superoxide dismutase activity and reducing malondialdehyde levels. Danthron also inhibited M1 macrophage polarization, preserved epithelial tight-junction proteins, and maintained transepithelial electrical resistance. CETSA, DARTS, and molecular docking confirmed direct engagement of Danthron with components of both the EGFR–PI3K–AKT and Nrf2–HO-1 pathways. In vivo, Danthron significantly ameliorated DSS-induced colitis, reducing inflammatory cytokines, epithelial apoptosis, oxidative stress, and myeloid cell infiltration while improving mucosal architecture and enhancing organoid regenerative capacity. These findings demonstrate that Danthron exerts potent antioxidant and anti-inflammatory effects through coordinated inhibition of EGFR–PI3K–AKT signaling and activation of the Nrf2–HO-1 axis, suggesting its promise as a multi-target therapeutic candidate for IBD. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related deaths in advanced disease, and activating KRAS/NRAS mutations limit the use of anti-EGFR antibodies to RAS–wild-type tumors. The cellular prion protein (PrP^C) has been linked to aggressive and chemoresistant CRC, but its extracellular partners and functional relevance in KRAS-mutant disease are not fully defined. Here, we examined extracellular PrP^C complexes and PrP^C-associated signaling in CRC cell lines and xenografts using a neutralizing PrP^C monoclonal antibody. Across a CRC panel that included SNU-C5/WT and its 5-fluorouracil- and oxaliplatin-resistant derivatives, HT-29 (KRAS–wild-type), and HCT-8 and LoVo (KRAS-mutant), co-immunoprecipitation showed that PrP^C forms complexes with the 37/67 kDa laminin receptor (RPSA), with PrP^C–RPSA association particularly increased in KRAS-mutant HCT-8 and LoVo cells. PrP^C protein levels were higher in KRAS-mutant HCT-8, SW620, and SNU-407 cells than in HT-29, and PrP^C neutralization reduced viability in all four lines. Accordingly, we assessed upstream RAS activity and found that active RAS (RAS-GTP) was higher in KRAS-mutant cells than in HT-29, and PrP^C treatment was associated with reduced RAS-GTP levels. In the same KRAS-mutant setting, basal AKT phosphorylation exceeded that in HT-29, and PrP^C treatment lowered AKT phosphorylation without changing total AKT. Moreover, PrP^C treatment was associated with reduced ERK1/2 phosphorylation in KRAS-mutant cells, suggesting attenuation of downstream RAS pathway output. These signaling changes coincided with a decrease in the S-phase fraction and an increase in G1. In an HCT-8 (KRAS G13D) xenograft model, PrP^C monotherapy inhibited tumor growth in a dose-dependent manner, and 5-fluorouracil (5-FU) monotherapy produced an intermediate effect. The combination of PrP^C (10 mg/kg) and 5-FU (20 mg/kg) yielded the greatest tumor growth inhibition among the tested regimens. Consistent with this enhanced tumor control, immunofluorescence of xenograft tissues showed that PrP^C, particularly with 5-FU, reduced intratumoral PrP^C and PCNA and decreased CD31-positive microvessels and α-SMA–positive vessel structures. Taken together, these findings suggest that extracellular PrP^C supports RAS–AKT signaling, proliferation, and tumor-associated angiogenesis in KRAS-mutant colorectal cancer, and that PrP^C neutralization additively enhances 5-fluorouracil activity in KRAS-mutant models. The data provide a preclinical basis for evaluating PrP^C antibodies in combination with fluoropyrimidine-based regimens in patients with KRAS-mutant CRC. Full article

Background: Colorectal cancer (CRC) demonstrates substantial clinical and biological diversity across age groups, ancestral backgrounds, and treatment settings, alongside a rising incidence of early-onset disease (EOCRC). The mitogen-activated protein kinase (MAPK) pathway is a major driver of CRC development and therapy response; however, the distribution and prognostic value of MAPK alterations across distinct patient subgroups remain unclear. Methods: We analyzed 2515 CRC tumors with harmonized demographic, clinical, genomic, and treatment metadata. Patients were stratified by ancestry (Hispanic/Latino [H/L] vs. non-Hispanic White [NHW]), age at diagnosis (early-onset [EO] vs. late-onset [LO]), and FOLFOX chemotherapy exposure. MAPK pathway alterations were identified using a curated gene set encompassing canonical EGFR-RAS-RAF-MEK-ERK signaling components and regulatory nodes. Conversational artificial intelligence (AI-HOPE and AI-HOPE-MAPK) enabled natural language-driven cohort construction and exploratory analytics; findings were validated using Fisher’s exact testing, chi-square analyses, and Kaplan–Meier survival estimates. Results: MAPK pathway disruption demonstrated marked heterogeneity across ancestry and treatment contexts. Among EO H/L patients, FGFR3, NF1, and RPS6KA6 mutations were significantly enriched in tumors not receiving FOLFOX, whereas PDGFRB alterations were more frequent in FOLFOX-treated EO H/L tumors relative to EO NHW counterparts. In late-onset H/L disease, NTRK2 and PDGFRB mutations were more common in non-FOLFOX tumors. Distinct MAPK-associated alterations were also observed among NHW patients, particularly in non-FOLFOX settings, including AKT3, FGF4, RRAS2, CRKL, DUSP4, JUN, MAPK1, RRAS, and SOS1. Survival analyses provided borderline evidence that MAPK alterations may be linked to improved overall survival in treated EO NHW patients. Conversational AI markedly accelerated analytic throughput and multi-parameter discovery. Conclusions: Although MAPK alterations are pervasive in CRC, their distribution varies meaningfully by ancestry, age, and treatment exposure. These findings highlight NF1, MAPK3, RPS6KA4, and PDGFRB as potential biomarkers in EOCRC and H/L patients, supporting the need for ancestry-aware precision oncology approaches. Full article

HIV/AIDS continues to pose a significant global public health concern, with Sub-Saharan Africa having the highest number of people living with HIV (PLHIV). Traditional medicines have been increasingly essential in treating and managing PLHIV. Product Nkabinde (PN), a polyherbal formulation derived from traditional medicinal plants, has recently demonstrated significant potential in the treatment of HIV. This study aims to elucidate the molecular mechanisms underlying the therapeutic effects of phytochemicals identified from PN in HIV treatment, utilizing network pharmacology and molecular docking. The intersecting (common) genes of the 27 phytochemicals of PN and HIV were computed on a Venn diagram, while the protein–protein interaction (PPI) network of the intersecting genes was plotted using STRING. The hub (10) genes were computed and analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways using ShinyGO. Molecular docking and protein–ligand interaction analysis of the 27 phytochemicals with each of the 10 hub genes were performed using the Maestro Schrodinger suite. The KEGG analysis reveals an important network with lower False Discovery Rate (FDR) values and higher fold enrichment. The pathway enrichments reveal that the 10 hub genes regulated by PN focus on immune regulation, metabolic modulation, viral comorbidity, carcinogenesis, and inflammation. GO analysis further reveals that PN plays key roles in transcription regulation, such as miRNA, responses to hormones and endogenous stimuli, oxidative stress regulation, and apoptotic signalling, kinase binding, protein kinase binding, transcription factor binding, and ubiquitin ligase binding enriched pathways. Consequently, molecular docking unveils complexes with higher binding energies, such as rutin-HSP90AA1 (−10.578), catechin-JUN (−9.512), quercetin-3-O-arabinoside-AKT1 (−9.874), rutin-EGFR (−8.127), aloin-ESR1 (−8.585), and quercetin-3-0-β-D-(6′-galloyl)-glucopyranoside-BCL2 (−7.021 kcal/mol). Overall, the results reveal pathways associated with HIV pathology and possible anti-HIV mechanisms of PN. Therefore, further in silico, in vitro, and in vivo validations are required to substantiate these findings. Full article

Glioblastoma (GBM) is characterized by its unique molecular features, such as self-renewal and tumorigenicity of glioma stem cells that promote resistance, largely resulting in treatment failure. Among the molecular alterations significant to GBM biology and treatment, mutations in isocitrate dehydrogenase (IDH) have assumed particular relevance. IDH-mutant and IDH-wild-type tumors exhibit significantly different metabolic characteristics, clinical behavior, and therapeutic sensitivities, making IDH status a critical determinant in determining prognosis and treatment strategies for GBM. In the context of cancer, chaperones were shown to promote tumor progression by supporting malignant cells over healthy ones. While heat shock proteins (HSPs) have long been implicated in the molecular mechanisms of tumor phenotype progression, recent attention has turned to CCT (chaperonin containing TCP1), orchestrating proteostasis. The chaperonin CCT is being explored as a diagnostic and therapeutic target in many cancers, including GBM, owing to its involvement in key oncogenic signaling pathways such as Wnt, VEGF, EGFR, and PI3K/AKT/mTOR. However, its role in the GBM-tricarboxylic acid (TCA) cycle cascade is still not well understood. Therefore, the present review highlights the potential role of the CCT complex in regulating hypoxia-inducible factor (HIF) activation by modulating enzymes responsive to metabolites derived from glucose metabolism and the TCA cycle in a manner dependent on oxygen availability and IDH mutation status. Full article

Background/Objectives: Mecasin (KCHO-1) is a standardized multi-herb formulation containing diverse bioactive compounds predicted to engage multiple molecular targets. This study applied an integrative network pharmacology approach to explore how Mecasin may interact with Alzheimer’s disease (AD)-related molecular networks. Methods: Bioactive constituents from 9 herbs were screened through OASIS and PubChem, and their predicted targets were cross-referenced with 8886 AD-associated genes from GeneCards. Overlapping genes were analyzed using protein–protein interaction mapping, Gene Ontology, and KEGG to identify potential Mecasin–AD core nodes and pathways. Co-expression, co-regulation, and molecular docking analyses were performed to further characterize mechanistic relevance. Results: Network integration identified 6 core genes—AKT1, STAT3, IL6, TNF, EGFR, and IL1B—positioned within signaling pathways related to neuronal survival, inflammatory regulation, and cellular stress responses, including FoxO, JAK–STAT, MAPK, and TNF pathways. Molecular docking suggested that several Mecasin compounds may interact with targets such as AKT1 and TNF. Conclusions: These in silico findings indicate that Mecasin, a multi-component formulation containing numerous phytochemicals that generate broad compound–target associations, may interface with interconnected neuroimmune pathways relevant to AD. While exploratory, the results highlight potential multi-target mechanisms that merit further investigation and provide a systems-level framework to inform future experimental validation. Full article

HER2 (human epidermal growth factor receptor 2) is a receptor tyrosine kinase which is overexpressed in ~20% of patients with oesophagogastric adenocarcinoma (EGA). HER2 represents a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, which plays a crucial role in cell proliferation, survival, and differentiation. HER2 significantly influences the tumour microenvironment (TME) through various mechanisms, creating a niche that supports tumour progression, immune evasion, and therapeutic resistance. In HER2-positive EGA, aberrant signalling pathways, such as PI3K/AKT and MAPK/ERK, enhance tumour cell survival and proliferation, whilst upregulation of angiogenic factors like VEGF fosters vascularization, meeting a tumour’s metabolic demands and facilitating its proliferation. HER2 also modulates the tumour immune microenvironment (TIME) by downregulating MHC molecules and recruiting immunosuppressive cells, including regulatory T-cells (T-reg) and tumour-associated macrophages (TAMs), which release cytokines that further inhibit anti-tumour immune responses. Together, these factors foster a pro-inflammatory, immunosuppressive microenvironment that underpins resistance to HER2-targeted therapies. As more HER2-directed treatments become available, such as trastuzumab–deruxtecan (T-DXd), gaining a deeper understanding of the multifaceted influence of HER2 on the TME in EGA will be crucial for the development of improved targeted treatments that can overcome these challenges and lead to advancements in targeted treatment for HER2-overexpressing EGA. This review provides a comprehensive overview of the impact of HER2 on the TME in EGA and highlights the challenge it represents as well as the opportunity for novel therapeutic development and the implications for patients in terms of clinicopathological outcomes. Full article

The substantial interest in plant-based drugs or plant-derived phytocompounds drives researchers to conduct comprehensive investigations on their therapeutic properties. Mollugin, one of the major active constituents of Rubia cardifolia, has been well-studied for its pharmacological properties, demonstrating potent anti-inflammatory properties by suppressing the TAK-1-mediated activation of NF-κB/MAPK and enhancing the Nrf2/HO-1-mediated antioxidant response. It exhibits strong anticancer effects through ferroptosis via IGF2BP3/GPX4 pathways, induces mitochondrial apoptosis, and targets NF-κB, ERK, and PI3K/Akt/mTOR to suppress tumor progression. Mollugin also inhibits JAK2/STAT and PARP1 pathways, suppressing IL-1β expression via the modulation of ZFP91. Moreover, it regulates the MAPK/p38 pathway, promotes neuroprotection, and improves cognitive performance through GLP-1 receptor activation. Mollugin promotes osteogenesis by activating the BMP-2/Smad1/5/8 signaling pathway and downregulates MAPK, Akt, and GSK3β expression, leading to the inhibition of osteoclastogenesis. It overcomes multidrug resistance by downregulating MDR1/P-gp, CREB, NF-κB, and COX-2 through AMPK activation. Its antibacterial effect is mediated by strong binding to FUR, UDP, and IpxB proteins in Enterobacter xiangfangensis. Mollugin mitigates Klebsiella pneumoniae infection, suppresses adipogenesis without causing cytotoxicity, and protects endothelial cells via the BDNF/TrkB-Akt signaling pathway. Synthetic derivatives of mollugin, such as oxomollugin and azamollugin, have shown enhanced anticancer and anti-inflammatory effects by regulating EGFR, PKM2, TLR4/MyD88/IRAK/TRAF6, and NF-κB/IRF3 pathways with improved solubility and stability. Collectively, these findings emphasize the broad-spectrum activity of mollugin. This review provides a critical interpretation of the mechanistic pathways regulated by mollugin and its derivatives, emphasizing their pharmacological significance and exploring their potential for future translation as multitarget drug candidates. Full article

Panacis Japonici Rhizoma (PJR), a medicinal and edible herb of the Panax genus, exhibits enhanced anti-lung cancer activity after steaming, a phenomenon consistent with other Panax species. However, the active constituents responsible for this improved efficacy and their underlying mechanisms remain unclear. In this study, we integrated UPLC-Q-TOF-MS–based metabolomics, network pharmacology, molecular docking, molecular dynamics simulations, and in vitro assays to identify the key metabolites and elucidate the mechanistic basis of steamed PJR against lung cancer. Metabolomic analysis revealed ten significantly upregulated metabolites following steaming. Network pharmacology analysis identified AKT1, EGFR, HSP90AA1, SRC, and STAT3 as core targets, primarily enriched in the MAPK, PI3K-Akt, and Ras signaling pathways. Molecular docking and molecular dynamics simulations further demonstrated stable interactions between major metabolites and core targets. In vitro experiments confirmed that steamed PJR exerted markedly stronger anti-tumor effects than its raw form. Collectively, these findings indicate that steamed PJR acts through a multi-target, multi-pathway mechanism mediated by multiple bioactive constituents, highlighting its therapeutic potential in lung cancer treatment. Full article

Background: Psoriasis is a chronic inflammatory skin disease driven by keratinocyte hyperproliferation and immune dysregulation. Despite the availability of biologics and immunosuppressants, recurrence and adverse effects remain major limitations. Myricetin (Myr), a natural flavonoid with well-documented anti-inflammatory and immunomodulatory properties, has shown promise in inflammatory disorders; however, its efficacy and mechanisms in psoriasis have not been fully elucidated. Methods: The therapeutic effects of topical Myr (0.5–2%) were evaluated in an imiquimod (IMQ)-induced psoriatic mouse model. Network pharmacology and molecular docking were employed to predict potential targets, followed by validation using histological analysis, cytokine profiling, qPCR, and Western blotting. Results: Network analysis identified 52 overlapping targets between Myr and psoriasis, including TNF, PTGS2, MMP9, and EGFR, with enrichment in TNF, IL-17, and PI3K/AKT signaling pathways. Myr treatment significantly alleviated IMQ-induced erythema, scaling, and epidermal thickening, improved skin-barrier function, and reduced the expression of IL-6, IL-17A, and TNF-α. Molecular docking showed strong binding affinities of Myr with TNF, PTGS2, MMP9, and EGFR. Western blotting confirmed that Myr suppressed EGFR and AKT phosphorylation and downregulated Mmp9, Ptgs2, and Tnf expression. Conclusions: Myr exerts multi-target anti-psoriatic effects by inhibiting the EGFR/AKT axis and inflammatory mediators, highlighting its potential as a safe and effective natural therapeutic agent for psoriasis. Full article

Biebersteinia heterostemon is a traditional Tibetan medicine known for its antioxidant, hypoglycemic, and anti-atherosclerotic properties. However, its therapeutic effects and mechanisms in the treatment of hyperlipidemia remain unclear. In this study, the ethyl acetate extract of B. heterostemon (BHEE) was first identified as the most effective lipid-lowering fraction through its inhibitory activity on pancreatic lipase and cholesterol esterase. Chemical characterization of BHEE by UHPLC-MS/MS revealed 108 compounds. Network pharmacology and molecular docking analyses were then employed to predict key active components and signaling pathways involved in BHEE’s lipid-lowering effects. A total of 50 active components and 623 targets were selected from the PubChem, SwissADME, and Swiss Target Prediction databases. These targets were intersected with 1606 hyperlipidemia-related targets from GeneCards, OMIM, and DrugBank, resulting in 144 common targets. The “drug-active component-intersecting target-pathway-HLP” and protein–protein interaction (PPI) networks suggested key active components such as 6-methoxytricin, vulgarin, flazin, ganhuangenin, and eupatorin, and core targets including TNF, IL6, AKT1, PPARG, and EGFR. GO and KEGG pathway enrichment analysis highlighted potential signaling pathways, such as AGE-RAGE, PPAR, insulin resistance, TNF, and lipid and atherosclerosis pathways. Molecular docking further predicted the strong binding affinity between key active components and core targets. At the cellular level, BHEE dose-dependently reduced lipid accumulation in FFA-induced HepG2 cells and improved oxidative stress (CAT, GSH, SOD, MDA) and inflammation (TNF-α, IL-6) markers. In conclusion, BHEE may exert its anti-hyperlipidemic effects through modulation of key targets like TNF, IL6, AKT1, PPARG, and EGFR. These findings suggest a multi-target mechanism, though further experimental validation is necessary to confirm these effects. This study provides valuable insights into the potential application of B. heterostemon as a natural therapeutic agent for hyperlipidemia. Full article

Background/Objective: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) lacking targeted therapies and characterized by high tumor heterogeneity. In this study, we evaluated the anticancer activity and mechanistic profile of Simalikalactone D (SKD), a quassinoid compound derived from the endemic Puerto Rican tree Simarouba tulae, in three TNBC cell lines, MDA-MB-468, MDA-MB-231, and SUM-149. Methods: MDA-MB-468, MDA-MB-231 and SUM-149 TNBC cells were evaluated for cell viability, proliferation and migration following SKD treatment. Phospho-antibody array, proteomics, and Western blot analyses were used to explore the SKD mechanism of action in MDA-MB-468 and MDA-MB-231 cell lines. Molecular docking was performed to assess SKD’s interaction with potential intracellular targets. Results: SKD exerted a concentration-dependent effect on the three cell lines. However, MDA-MB-468 cells exhibited an IC₅₀ of 67 nM, while the IC₅₀ values for MDA-MB-231 and SUM-149 were 422 nM and 598 nM, respectively. In MDA-MB-468 cells, 100 nM of SKD induced apoptosis, evidenced by the activated caspase-3 activity, PARP-1 cleavage and decrease in Bcl-2 and survivin protein levels. Sublethal SKD (25 nM) impaired migration in MDA-MB-231 cells and reduced proliferation and motility in SUM149 cells. A 6 h SKD treatment markedly reduced phosphorylation of apoptosis-related proteins (p53, BAD, DAXX, AKT1, JUN) and Jak/STAT pathway components, indicating early disruption of intracellular signaling prior to phenotypic changes. Proteomic profiling showed distinct pathway alterations in both MDA-MB-468 and MDA-MB-231 cells, with reduced Integrin β1 (ITGB1) levels emerging as a shared effector. This suggests that SKD broadly disrupts cell adhesion and migration independently of apoptosis-driven cell death. Western blot validation confirmed reduced ITGB1 protein levels across all three TNBC cell lines examined. In silico docking confirmed favorable binding affinities of SKD to both EGFR (ΔG = −6.718 kcal/mol) and STAT4 (ΔG = −8.481 kcal/mol). Conclusions: Overall, our findings suggest that SKD is a potent anticancer agent in a subgroup of TNBC cells. Full article

Background/Objective: Eclipta prostrata (L.) L. is a traditional medicinal herb utilized throughout Asia that is widely used for hepatoprotective activity, wound healing, and blood cooling/bleeding disorders. This work aimed to identify bioactive constituents from E. prostrata collected in Vietnam, and clarify their anti-inflammatory capacity of the extract and active fraction. Method: Extraction and isolation of compounds from the extract of E. prostrata were performed. The extract, fractions, and isolated compounds were evaluated for inflammatory cytokines in LPS-stimulated RAW264.7 cells. Isolates showed inflammatory potential by in silico approaches. Results: Thirteen compounds, comprising a first isolated compound (diosmin), flavonoids, and phenolic derivatives, were separated and identified. The protein–protein interaction (PPI) network demonstrated TNF, IL6, AKT1, NFKB1, EGFR, and PTGS2 as central targets, highlighting their significance in inflammatory signaling. Gene Ontology and KEGG pathway enrichment underscored substantial participation in TNF and IL-17 cytokine signaling pathways. Molecular docking demonstrated robust interactions between several flavonoids and core targets, indicating their function as essential regulators. Experimental validation in LPS-stimulated RAW264.7 macrophages revealed that wedelolactone, luteolin, apigenin, and quercetin significantly inhibited TNF-α and IL-6 production. Conclusions: The results proposed that E. prostrata demonstrates its anti-inflammatory efficacy via a multi-target, poly-pharmacological strategy that encompasses central cytokine pathways and upstream receptor-mediated signaling. Our findings offer new mechanistic evidence that supports the ethnomedicinal application of E. prostrata and indicates its potential as a valuable natural resource for treating anti-inflammatory diseases. Full article

Galectin-3 (Gal-3) is a histologic marker of pancreatic cancer and a potential therapeutic target. This study aimed to characterize a novel sulfated agarose-derived oligosaccharide (DP9) from marine algae, Gracilaria lemaneiformis, evaluate its Gal-3 inhibitory activity, and investigate its anti-pancreatic cancer mechanisms. Through controlled acid hydrolysis, a series of odd-numbered oligosaccharides (DP3-11) were obtained, in which DP9 showed the strongest Gal-3 inhibition in hemagglutination assays. Structural analysis confirmed DP9’s unique composition including an alternating β (1→4)-D-galactose and α (1→3)-3,6-anhydro-L-galactose backbone, featuring partial 6-O-methylation on β-D-galactose and 6-O-sulfation on 3,6-anhydro-α-L-galactose residues. Molecular docking revealed DP9’s binding to Gal-3’s carbohydrate recognition domain through key hydrogen bonds (His158, Arg162, Lys176, Asn179 and Arg186) and hydrophobic interactions (Pro117, Asn119, Trp181 and Gly235), with the sulfate group enhancing binding affinity. In vitro studies demonstrated DP9’s selective anti-pancreatic cancer activity against BxPC-3 cells, including inhibition of cell proliferation; S-phase cell cycle arrest; induction of apoptosis; and suppression of migration and invasion. Mechanistically, DP9 attenuated the Gal-3/EGFR/AKT/FOXO3 signaling pathway while showing minimal cytotoxicity to normal cells. This study first demonstrated that agarose-derived odd-numbered oligosaccharides (DP9) can serve as effective Gal-3 inhibitors, which proved its potential as a marine oligosaccharide-based therapeutic agent for pancreatic cancer. Full article