Search Results (763)

Keloid is a benign skin disease with excessive growth of fibroblasts, characterized by too much abnormal extracellular matrix deposited in the dermis. It is generally believed that transforming growth factor-β (TGF-β) is the core cytokine that causes keloid. Previously, it was thought that its pathogenic effect was mainly attributed to the classical Smad-dependent pathway. It directly shuttles signals to the nucleus to trigger pro-fibrotic gene transcription. However, accumulating evidence now points to the equally vital role of Smad-independent signaling. Unlike the direct nuclear translocation of Smads, these alternative pathways transmit signals through rapid intracellular kinase cascades. They jointly direct the proliferation, migration, anti-apoptosis, fibrogenesis, and chronic inflammation of fibroblasts in keloids. This review attempts to comprehensively clarify the molecular processes regulated by TGF-β through non-Smad pathways (such as MAPK, PI3K/Akt, Rho GTPase, Wnt/β-catenin, JAK/STAT). Translating these non-Smad insights helps to overcome the high recurrence rates of traditional therapies. Targeting these specific molecular hubs through combination and precision therapies serves to reprogram the fibrotic microenvironment. Full article

Background: Hepatitis B virus (HBV) infection continues to be a major public health concern, especially in sub-Saharan Africa, where widespread epidemics and restricted availability of long-term antiviral therapies result in higher mortality and morbidity rates. Drug repurposing represents a strategic approach to accelerate the discovery of effective therapies by leveraging agents with demonstrated antiviral and immunomodulatory activity. Product Nkabinde (PN) is a patented African polyherbal formulation initially developed for the treatment of HIV. Recent experimental studies demonstrate PN’s potent anti-HIV activity and significant immunomodulatory effects in human immune cells, implicating host-directed mechanisms relevant to chronic viral infections. This study combines an integrative application of network pharmacology and molecular docking to evaluate the repurposing potential of PN as a multi-target agent in HBV. Method: Bioactive components of PN were screened, and compound-associated targets were intersected with HBV-associated genes (proteins) to construct a protein–protein interaction (PPI) network. Topological analysis identified 10 hub targets (STAT1, STAT3, SRC, HCK, EGFR, SYK, PIK3CA, PIK3CB, PIK3R1, and PTPN11). Gene Ontology and KEGG pathway enrichment were performed with an FDR cut-off < 0.05. Significantly enriched pathways included JAK–STAT signaling, chemokine signaling, EGFR-TKI resistance, PI3K complex signaling, and viral infection pathways, particularly those related to Kaposi sarcoma virus and HSV-1, indicating immunoregulatory and antiviral roles. Molecular docking was performed using AutoDock Vina 1.1.2 to evaluate binding affinity and interaction mode of key PN phytochemicals against the hub proteins, and results were compared to their respective co-crystallized ligands. Results: Molecular docking indicated that major phytochemicals from PN exhibited significant binding affinities across all 10 hub host targets, typically outperforming or closely matching their respective co-crystallized ligands. The strongest contacts were observed for β-sitosterol–PIK3CB (−14.2 kcal/mol) and oleanolic acid–SYK (−14.0 kcal/mol), which were significantly stronger than the co-crystallized ligands (−7.9 and −8.3 kcal/mol, respectively), indicating robust stabilization within catalytic and regulatory pockets. Procyanidin B2 toward HCK (−10.5 vs. −7.9 kcal/mol) and PIK3CA (−9.5 vs. −7.3 kcal/mol), quercetin toward PIK3R1 (−10.6 vs. −8.2 kcal/mol) and PTPN11 (−9.2 vs. −7.5 kcal/mol), rutin toward SRC (−10.5 vs. 7.8 kcal/mol), and diosgenin toward EGFR (−9.4 vs. 8.4 kcal/mol). Procyanidin B2 maintained robust multi-hydrogen bonding networks, demonstrating significant binding, despite STAT1 and STAT3 docking showing identical affinities to co-crystals. Conserved hydrogen bonds, π–cation interactions, and significant hydrophobic packing at ATP-binding clefts and regulatory domains supported these interaction patterns, indicating competitive suppression of host signaling nodes taken over by HBV. Conclusions: Together, these results demonstrate that the components of PN possess strong multitarget binding capabilities across the PI3K/AKT, JAK–STAT, SRC-family kinase, EGFR, and SYK pathways, supporting their potential repurposing as host-directed HBV therapeutics with the ability to impede immune evasion, viral persistence, and HBV-associated oncogenic progression. Full article

Background/Objectives: Inflammatory mediators within the tumor microenvironment contribute to lung cancer progression by enhancing cellular motility and invasive capacity through cytokine-dependent signaling networks. Modulation of these inflammation-associated pathways by dietary bioactive compounds may provide complementary strategies for limiting cancer aggressiveness. Our objective was to examine the inhibitory effects of a cyanidin-3-O-glucoside (C3G)-rich fraction from Kum Akha pigmented black rice (CKAB-P1) on inflammation-stimulated A549 cancer cell progression. Methods: CKAB-P1 was obtained through solvent-partition extraction and chemically characterized using the pH differential method and high-performance liquid chromatography. A549 cells were pretreated with CKAB-P1 or C3G, followed by stimulation with conditioned medium predominantly containing IL-6 and IL-1β derived from LPS-exposed THP-1 macrophages (THP-1-CS). Effects on cancer cell migration and invasion were evaluated using wound-healing, Transwell invasion, gelatin zymography, and Western blot analyses. Results: CKAB-P1 contained 106.62 ± 3.54 mg/g extract of total anthocyanins, with C3G representing the major constituent (59.42 ± 2.54 mg/g extract). Exposure of THP-1-CS stimulated migration and invasion of A549 lung cancer, and neutralization of IL-6 and IL-1β reduced these pro-migratory effects, confirming cytokine involvement. Treatment with CKAB-P1 (10–40 μg/mL) or C3G (2.5–20 μg/mL) markedly attenuated inflammation-enhanced migration and invasion (p < 0.05). A reduction in MMP-2 and MMP-9 activity, along with decreased expression of invasion-associated protein expressions (uPA, uPAR, and MT1-MMP), was observed. Furthermore, both CKAB-P1 and C3G attenuated phosphorylation of JAK1 and STAT3. Conclusions: These findings suggest that anthocyanin-enriched black rice fraction may limit inflammation-driven A549 lung cancer cell aggressiveness through modulation of the cytokine-driven JAK1/STAT3 signaling cascade, indicating its potential relevance as a bioactive dietary component targeting tumor-associated inflammatory signaling. Full article

Periodontitis represents a primary etiological factor in tooth mobility, with oxidative stress contributing critically to periodontal tissue destruction. Evodiamine (EVO), a quinazolinocarboline alkaloid, exhibits multiple biological activities; however, its antioxidant effects and mechanism in periodontitis have not been elucidated. The aim of this study was to investigate the regulatory effect of EVO on oxidative stress in periodontitis and to explore the associated molecular mechanism. The results indicate that EVO exhibits potent antimicrobial activity against key periodontal pathogens and suppresses pathogen-induced ROS generation as well as the release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) under periodontitis conditions. EVO binds specifically to the Kelch domain of KEAP1 with a strong binding energy (−11.67 kcal/mol), inhibits KEAP1–NRF2 interaction, and consequently upregulates the expression of antioxidant enzymes (HO-1, NQO1, GCLC, and SOD2), while downregulating the expression of iNOS, COX2, and NOX2. Furthermore, EVO inhibits the pro-apoptotic effect of the JAK2/STAT3 signaling axis and mitigates inflammation, alleviates cell cycle arrest, and promotes the migration and repair of periodontal ligament cells. Collectively, these findings suggest that EVO acts as a potential binder of KEAP1 that alleviates periodontal inflammation through modulation of oxidative stress and regulation of the JAK2/STAT3 pathway. Full article

This study conducted a 70-day feeding trial to evaluate the effects of dietary Lactobacillus plantarum supplementation (0, 0.1, 1.0, and 10.0 g/kg) in red claw crayfish (Cherax quadricarinatus). Growth performance, hepatopancreatic antioxidant-related parameters, and the expression of genes related to the Toll/Imd and JAK-STAT pathways were determined. Results showed that dietary L. plantarum supplementation significantly improved weight gain rate, specific growth rate, daily growth index, and feed efficiency, which were increased by 23.57%, 5.10%, 9.67%, and 7.90%, respectively, and reduced mortality rate by 60.00% compared with the control group (p < 0.05), enhanced the activities of glutathione peroxidase, catalase, superoxide dismutase and total antioxidant capacity, and reduced malondialdehyde levels in the hepatopancreas (p < 0.05). Furthermore, dietary L. plantarum supplementation was associated with the upregulated expression of key genes related to the Toll/Imd and JAK-STAT signaling pathways (p < 0.05). The expression levels of tumor necrosis factor-α, interleukin-1β, and transforming growth factor-β1 were also significantly increased (p < 0.05). Overall, these findings suggest that dietary L. plantarum supplementation improved growth performance and antioxidant-related and immune-related parameters in red claw crayfish, and that these effects were associated with the upregulated expression of genes involved in the Toll/Imd and JAK-STAT pathways. Among the tested treatments, 1.0 g/kg L. plantarum produced the most favorable overall response. Full article

Histone deacetylase 6 (HDAC6), a member of the class IIb HDAC family, plays a crucial role in epigenetic regulation and cytoskeletal dynamics, while participating in host anti-infective immune responses. However, its precise functions and mechanisms during Chlamydia muridarum (C. muridarum) infection remain incompletely defined. Our study demonstrated that C. muridarum respiratory infection upregulates HDAC6 expression at the infection site and in immune organs. Comparative analysis of wild-type (WT) and HDAC6-deficient (HDAC6^−/−) mice in this infection model revealed that HDAC6 deficiency exacerbates disease progression, including significant weight loss, severe pulmonary inflammation, and impaired C. muridarum clearance. Relative to WT mice, HDAC6^−/− mice exhibited elevated Signal Transducer and Activator of Transcription 6 (Stat6) and GATA Binding Protein 3 (Gata3) mRNA expression, enhanced pathological Th2 responses with increased IL-4 secretion, and no significant differences in protective Th1 or Th17 responses following C. muridarum infection. Concurrently, these mice displayed enhanced M2 macrophage polarization, as evidenced by upregulated CD206 and Arg-1 expression, whereas M1 marker expression remained unchanged. The vitro studies confirmed that HDAC6^−/− bone marrow-derived macrophages (BMDMs) promote M2 polarization, characterized by increased Arg-1, IL-10, and TGF-β production, and further co-culture experiments showed that C. muridarum -stimulated HDAC6^−/− BMDMs drive Th2 differentiation. These findings elucidate the critical role of HDAC6 in regulating Th2-M2 immune responses during C. muridarum respiratory infection and suggest targeted modulation of HDAC6 as a novel therapeutic strategy for chlamydial respiratory infection. Full article

The programmed death-ligand 1 (PD-L1) plays a critical role for promoting cancer immune evasion. However, the resistance to PD-L1-targeted immunotherapy greatly limits its application. α-lipoic acid (ALA) is an endogenous antioxidant, while whether ALA affects PD-L1 expression remains unknown. In IFN-γ-stimulated castration-resistant prostate cancer (CRPC)-mimicking PC3 and DU145 cells, the expression of PD-L1 and its regulatory genes was determined by Western blotting, RT-PCR, and immunofluorescence. The T-cell-mediated tumor-killing activity was evaluated in a co-culture system of cancer cells and Jurkat T cells. ALA significantly inhibits IFN-γ-induced PD-L1 protein and mRNA expression without affecting its degradation. The upstream genes accounting for PD-L1 induction, including JAK1/STAT1/IRF-1 cascade, c-Myc, HIF-1α, and GSK3β activity, were markedly suppressed by ALA. The decreased expression of PD-L1 and these regulators by ALA is also modulated by attenuation of mTOR/p70S6K/4EBP1-dependent protein translation and ROS production. In the co-culture system, ALA markedly increased T-cell-mediated tumor-killing activity compared to that of ALA treatment alone, suggesting that ALA may augment the antitumor immunity. Collectively, we demonstrated that ALA-mediated inhibition of PD-L1 expression is regulated by multiple mechanisms, which indicates that ALA may be a potential agent to enhance cancer immunotherapy, particularly in CRPC. Full article

Endothelial dysfunction, chronic inflammation, immune dysregulation, oxidative stress, mitochondrial dysfunction, and metabolic disturbances collectively contribute to cardiovascular diseases (CVDs) associated with blood stasis patterns. Xuefu Zhuyu Decoction (XFZYD) is widely used clinically for the management of CVDs. Based on serum-exposed prototype profiling in rats, two pharmacology-driven core component sets of XFZYD were defined as the core set for the promotion of blood circulation and the elimination of blood stasis (CPBEB; HSYA, GRo, FA, β-ECD, AMY, ALB, PF) and the core set for the regulation of qi and the relief of pain (CRQRP; LIQ, NR, NAR, ROF, HSD, NHP, LTG, NRG, ISL, FNT, NOB, PD, SSa). CPBEB primarily targets vascular pathology by regulating endothelial dysfunction with dyslipidemia-driven arterial lipid deposition. Mechanistically, CPBEB is associated with improved endothelial function, reduced plaque instability, attenuated chronic inflammation and oxidative stress, normalized lipid and bile acid metabolism, and decreased thrombosis. CRQRP primarily modulates vascular tone and systemic energy metabolism. These effects are linked to enhanced AMPK/SIRT1-driven antioxidant defenses and mitochondrial homeostasis, increased NO/cGMP signaling, coordinated crosstalk among the TLR4/NF-κB, JAK/STAT, NLRP3, and PPAR pathways, and remodeling of the gut microbiota–immune network. In summary, this review integrates modern analytical approaches with network pharmacology and the literature evidence to clarify the material basis underlying XFZYD’s therapeutic effects in CVDs, thereby supporting the modernization and internationalization of traditional Chinese medicine. Full article

Impaired blood–brain barrier (BBB) integrity is a common hallmark of neurological disorders associated with neuroinflammation, neurodegeneration and aging. The function of the BBB relies heavily on the interaction between astrocytes and endothelial cells, the most closely connected elements of the neurovascular unit. Under inflammatory conditions, astrocytes can undergo a range of metabolic changes, becoming pro-inflammatory and harmful to endothelial cells. Upon activation, astrocytes secrete a plethora of inflammatory mediators that severely disrupt the barrier function of the BBB. ω-3 polyunsaturated fatty acids (PUFAs), mainly docosahexaenoic and eicosapentaenoic acids, exhibit protective anti-inflammatory and antioxidant effects demonstrated in various neurological disorders. This review focused on the role of ω-3 PUFAs and their oxidative derivatives, specialized pro-resolving mediators, in preserving the BBB’s integrity via suppression of astrocytes’ activation or even promotion of their transition from an A1 to an A2 phenotype. We considered mainstream mechanisms of the anti-inflammatory and antioxidant effects of ω-3 PUFAs on reactive astrocytes, such as stimulation of the Nrf2/ARE and Wnt/β-catenin signaling pathways, inhibition of NF-κB/matrix metalloproteinase activity and the JAK/STAT3 signaling axis, as well as the contribution of ω-3 PUFA-activated GPCRs and PPAR transcriptional factors, particularly regarding the role of these mechanisms in preserving the BBB’s integrity. Full article

To characterize the transcriptional and physiological alterations induced by manganese stress in Coilia nasus, juveniles (mean weight 5.0 ± 0.2 g) were subjected to either manganese exposure (5.50 ± 0.03 mg/L) or control (0 mg/L) for a 12 h period. Subsequently, gill tissues were excised for evaluation of antioxidant parameters and RNA-Seq analysis. A total of 753 DEGs were identified in the manganese exposure group compared to controls, comprising 287 up-regulated and 466 down-regulated genes. GO and KEGG enrichment analysis of DEGs showed that most of the DEGs were involved in immune and metabolic pathways, which disturbed the biological processes related to immunity and metabolism at the molecular level. The acute manganese stress initiated a multi-level antioxidant response to cope with oxidative stress in Coilia nasus. This finding was further supported by the significant increase in MDA content and significant decrease in GSH content and GSH-Px activity under manganese exposure, while SOD and CAT activities were significantly increased. Simultaneously, the acute manganese stress triggered profound metabolic reprogramming to cope with energy pressure in Coilia nasus, which showed that manganese exposure significantly down-regulated energy metabolism-related genes (pfkm, pgam2, eno3, pkm, aqp9, apoa1, tkt, sds); furthermore, the overall energy metabolism network was widely inhibited, while lipid metabolism-related genes (fabp3, cpt1a) were significantly up-regulated to compensatorily activate fatty acid transport and β-oxidation pathways. In addition, the acute manganese stress initiated a complex immune response pattern to cope with cell damage in Coilia nasus, which showed that manganese exposure significantly enhanced the expression of inflammatory signaling genes (mapk1, stat1, tgfb3); furthermore, certain inflammatory pathways were activated, while the expressions of immune regulatory genes (traf6, il-10) were significantly decreased. In summary, these results indicated that manganese exposure could impair immune function, disrupt metabolism, and induce oxidative stress in Coilia nasus. Full article

Glycogen synthase kinase-3 (GSK3) inhibition is a commonly used approach to promote osteogenic differentiation through activation of Wnt signaling. However, 6-bromoindirubin-3′-oxime (BIO), which is commonly used for GSK3 inhibition, also targets JAK/STAT, raising the possibility of dual pathway interference during osteoblast differentiation, as both GSK3 and JAK/STAT pathways are critical regulators of osteoblastogenesis. In this study, we investigated the effect of BIO on the osteoblast differentiation of hMSCs-TERT4. While BIO had no significant effect on cell viability or apoptosis, it markedly inhibited osteoblast differentiation, as evidenced by reduced ALP activity, decreased matrix mineralization, and downregulation of osteoblast-associated markers. Microarray analysis followed by qRT-PCR validation revealed downregulation of Wnt and TGF-β pathway genes. These findings show that BIO suppresses osteoblast commitment and osteogenic differentiation, accompanied by altered Wnt- and TGF-β-related gene expression. This study provides mechanistic insight into the off-target consequences of widely used small molecules and highlights the importance of dissecting pathway-specific roles in stem cell differentiation. Understanding the interplay between GSK3 and JAK signaling is essential for optimizing pharmacological strategies in skeletal regenerative medicine. This study highlights the importance of pathway selectivity when using small molecules in stem cell-based therapies for bone regeneration. Full article

Background: We evaluated the potential neuroprotective effects of naloxone in moderate traumatic brain injury (TBI), focusing on its ability to alleviate neuroinflammation, reduce cognitive impairment, and to influence Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling markers. Methods: Male C57BL/6J mice were used to establish an in vivo model of moderate TBI using a stereotaxic impactor. Immediately post-injury, naloxone was administered intraperitoneally (1 mg/kg/day) for 7 days. A total of 72 mice were divided into four groups: Normal, normal with naloxone, TBI, and TBI with naloxone (18 mice in each group). Immunohistochemical analyses and cognitive functions were evaluated across the groups. Results: TBI mice treated with naloxone exhibited significantly reduced brain swelling and cortical tissue loss compared to untreated mice. Naloxone reduced Transforming growth factor beta 2 (TGF-β2) and increased interleukin 11 (IL-11) expression in the brain. Additionally, levels of JAK2, STAT3, and B-cell lymphoma 2 (Bcl-2) were significantly elevated following treatment, while expressions of Tumor protein p53 (p53), Caspase 3, Microtubule-associated proteins 1A/1B light chain 3B (LC3B), and Sequestosome 1 (p62) were reduced. Fluorescence intensities of ionized calcium binding adaptor molecule (Iba-1) and dichloro-dihydro-fluorescein diacetate (DCFH-DA) were enhanced, indicating decreased microglial activation and reactive oxygen species (ROS) production due to naloxone treatment. Cognitive function tests revealed improved performance in TBI mice treated with naloxone, demonstrated by decreased alteration rates in the Y-maze test and improved preference index scores in the novel object recognition (NOR) test. Conclusions: Naloxone shows potential for neuroprotection and enhanced cognitive performances, which may be associated with modulation of JAK2/STAT3 signaling in a mouse model of moderate TBI. Full article

Acute Lymphoblastic Leukemia (ALL) is a heterogeneous hematological malignancy in which disease progression and response to therapy are influenced by a complex network of molecular alterations, interactions with the bone marrow microenvironment, and epigenetic modulation mechanisms. Crosstalk between oncogenic, inflammatory, and immunoregulatory signaling pathways, together with epigenetic modifications, contributes to the maintenance of leukemic survival and the development of therapeutic resistance. This review analyzes the role of cytokines and chemokines such as IL-6, TNF-α, and CXCL12, which act as biological biomarkers and key mediators of leukemia niche remodeling, and the main signaling pathways involved in ALL, such as Wnt/β-catenin, JAK/STAT, PI3K/AKT/mTOR, Notch, and BCR, highlighting their functional interconnection with the tumor microenvironment. The role of epigenetics in modulating the dialogue between leukemia cells and stromal components is also discussed. Epigenetic programs govern leukemia’s dependence on stromal support, inflammatory and niche-derived signals, as well as the microenvironment signaling pathways. Overall, targeting leukemia-niche interactions is a crucial strategy for improving outcomes in ALL and to identify potential molecular vulnerabilities, also for developing new therapeutic approaches for the treatment of the disease. Full article

Colorectal cancer (CRC) is a significant cause of cancer mortality in the world, and its etiology is complicated by genetic and epigenetic changes. As one of the most important tumor progression regulators, Zinc Finger E-box Binding Homeobox 1 (ZEB1) is a transcription factor that has a key role in epithelial–mesenchymal transition (EMT), which is essential in the metastasis, drug resistance, and plasticity of cancer cells in CRC. ZEB1 silences the expression of epithelial markers, including E-cadherin, and it induces the development of mesenchymal properties, such as invasion and metastasis, i.e., tumor aggressiveness. ZEB1 drives epigenetic reprogramming in CRC by coordinating histone deacetylation, histone methylation, and DNA methylation of epithelial tumor suppressor gene promoters and by engaging in reciprocal regulatory interactions with non-coding RNAs, including the miR-200 family. Furthermore, multiple oncogenic signaling cascades, including Wnt/β-catenin, TGF-β, NF-κB, MEK-ERK, JAK/STAT3, and HIF-1α, converge on ZEB1 to amplify its transcriptional and epigenetic activity, positioning ZEB1 as a nodal integrator of extracellular cues and epigenetic reprogramming in CRC metastasis. This review integrates three interconnected regulatory layers, i.e., (1) ZEB1’s direct epigenetic control of target gene expression via histone modification and DNA methylation, (2) post-transcriptional regulation of ZEB1 itself by ncRNAs (miRNAs, circRNAs, and lncRNAs) that create feedback circuits modulating layer 1, and (3) upstream modulation of ZEB1 transcriptional activity by oncogenic signaling pathways (Wnt/β-catenin, TGF-β, NF-κB, MEK-ERK, JAK/STAT3, and HIF-1α) to provide a comprehensive picture of ZEB1 in CRC metastasis and its therapeutic implications. Full article

Background: Chrysopogon zizanioides (L.) Roberty (vetiver) is a perennial medicinal grass with deep aromatic roots traditionally used for several ailments. Its root essential oil (CZEO) is rich in phytochemicals with documented antimicrobial, anti-inflammatory, and antioxidant activities. Although its anticancer potential remains underexplored, the complex phytochemical profile of CZEO positions it as a promising multi-target therapy, particularly for colorectal (CRC) and lung cancers where resistance and pathway redundancy often limit conventional treatments. Therefore, this study aimed to investigate the phytochemical composition and antiproliferative activity of CZEO from Qatar against colorectal (HCT-116) and lung (A549) cancer cells and to elucidate its molecular targets and mechanisms of action in CRC and lung cancer using network pharmacology and in silico approaches. Methods: CZEO was extracted by steam distillation and characterized using GC–MS. In vitro proliferation assays with HCT-116 colorectal and A549 lung cancer cells were conducted using the Alamar Blue assay. The ten most abundant phytochemicals identified by GC–MS were assessed for drug-likeness and ADMET properties and further analyzed through network pharmacology, molecular docking, and molecular dynamics (MD) simulations to elucidate the molecular targets and mechanisms underlying CZEO’s anticancer activity. Results: GC-MS profiling identified 40 compounds, predominantly sesquiterpenoids (93%), including khusimol, β-eudesmol, α-vetivone, and rosifoliol. CZEO inhibited cancer cell viability in a dose-dependent manner, with IC₅₀ values of 62.95 ± 2.19 µg/mL for HCT-116 and 167.82 ± 6.51 µg/mL for A549 cells, demonstrating greater potency against colorectal cancer. CZEO did not affect the growth of normal human neonatal fibroblasts (HDFn), suggesting potential selectivity for cancerous cells. ADMET predictions indicated favorable pharmacokinetics and low toxicity of CZEO’s top 10 abundant compounds (TACs). Network pharmacology revealed 373 and 394 overlapping gene targets between TACs and lung and colorectal cancer, respectively. The overlapping genes were used to construct a protein–protein interaction (PPI) network to identify hub genes. STAT3 and AKT1 consistently emerged as common top-scoring hub genes in both cancers. Molecular docking of TACs showed strong binding affinities of rosifoliol and α-vetivone to AKT1 (−6.20 and −5.93 kcal/mol, respectively) and STAT3 (−5.19 and −5.09 kcal/mol, respectively), surpassing reference inhibitors. MD simulations confirmed stable ligand–protein interactions and structural stabilization, particularly with α-vetivone. Conclusions: CZEO from Qatar exhibits potent antiproliferative activity against colorectal and lung cancer cells, supported by a sesquiterpenoid-rich phytochemical profile. Integrative computational analyses highlight AKT1 and STAT3 as key molecular targets, with rosifoliol and α-vetivone emerging as promising lead compounds. These findings support CZEO as a natural, multi-target anticancer agent, warranting further mechanistic and in vitro and in vivo validation. Full article