Search Results (269)

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

The tomato hind (Cephalopholis sonnerati) is a marine aquaculture fish species with high economic value. Elucidating the mechanisms underlying its growth regulation is crucial for the development of the aquaculture industry. To analyze the biological mechanisms underlying growth differences, individuals with extreme body sizes at 8 months of age from the same batch were selected in this study. A combined experiment of “body size × feeding status” was constructed, and transcriptome sequencing and weighted gene co-expression network analysis (WGCNA) were performed on brain and muscle tissues. The results showed that 2553 differentially expressed genes (DEGs) were identified between individuals with distinct body sizes, which were significantly enriched in growth regulation pathways such as PI3K–Akt, MAPK, and FoxO. Feeding differences affected 4480 genes, which were significantly enriched in signaling pathways including the insulin signaling pathway. WGCNA further identified co-expression modules (brown4, blue, coral1) significantly correlated with growth, as well as hub genes including pik3r1 and eif4ebp2. Comprehensive analysis demonstrated that the growth regulation of C. sonnerati operates as a cascade network. Brain tissues perceive signals through neuroactive ligand–receptor interactions and integrate and transduce these signals via core pathways including Ras–MAPK and PI3K–Akt. Finally, growth processes are executed in muscle tissues by regulating glycogen metabolism, protein synthesis, and other processes, which are precisely regulated by terminal processes such as cellular senescence. Among them, pik3r1 and eif4ebp2, as key molecular switches, play a central role in integrating upstream signals and precisely regulating downstream growth programs. This study preliminarily clarifies the molecular mechanism network of growth differences in C. sonnerati, providing a theoretical basis and candidate genes for the genetic improvement of its growth traits. Full article

Alpha-mangostin (AM), a xanthone from Garcinia mangostana, has shown promising nephroprotective properties, but its mechanisms in acute kidney injury (AKI) remain incompletely defined. In this study, we applied an integrative network pharmacology pipeline combined with molecular docking to clarify AM’s multi-target mechanisms in AKI. We identified 128 predicted AM targets and intersected them with AKI-related genes, yielding 122 shared targets. Protein–protein interaction analysis identified ten hub genes—TNF, AKT1, IL6, SRC, CTNNB1, HSP90AA1, NFKB1, HIF1A, PPARG, and PTGS2—implicating inflammatory, hypoxia, and cell-survival pathways. KEGG enrichment highlighted HIF-1 signaling, PI3K–Akt signaling, chemokine signaling, AGE–RAGE signaling, and pathways related to cellular senescence and oxidative stress, while GO terms emphasized responses to chemical/oxygen-containing compounds, kinase activity, signal transduction, and apoptosis. Molecular docking against the ten hub proteins showed favorable binding energies across multiple targets. The strongest predicted affinities were observed for PTGS2 (−11.13 kcal/mol), TNF (−9.74 kcal/mol), and AKT1 (−9.48 kcal/mol). Docking positioned AM within the COX-2 catalytic pocket, engaging key catalytic and hydrophobic residues similar to known inhibitors. MD simulation interaction analysis confirmed that AM maintained stable contacts with key human PTGS2 residues, characterized by dominant hydrogen bonds and water-bridge interactions with SER353, TYR355, ARG513, and SER530, along with consistent hydrophobic contacts, and persistent interactions sustained throughout the 200 ns trajectory. Collectively, these results suggest that AM modulates interconnected inflammatory, hypoxic, and survival pathways relevant to AKI, acting as a multi-target ligand with notable interaction involving COX-2, TNF, and AKT1. Further experimental validation and formulation strategies to improve bioavailability are recommended for the advancement of AM toward therapeutic evaluation in AKI. Full article

Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, with nearly one quarter of patients presenting with metastatic disease at diagnosis. The epidermal growth factor receptor (EGFR) plays a central role in CRC pathogenesis through activation of downstream RAS/RAF/MAPK and PI3K/AKT/mTOR signaling pathways, and has become a major therapeutic target. Anti-EGFR monoclonal antibodies, cetuximab and panitumumab, have demonstrated survival benefit in selected patients, particularly those with left-sided, RAS wild-type tumors. However, primary and acquired resistance limit their efficacy, underscoring the need for predictive biomarkers and novel strategies. This review synthesizes current knowledge of EGFR biology, therapeutic integration, and biomarker development, including RAS and BRAF mutations, MSI status, HER2 amplification, EGFR ligands (AREG/EREG), consensus molecular subtypes, and liquid biopsy applications. We also discuss mechanisms of resistance such as pathway reactivation, receptor mutations, and epithelial-to-mesenchymal transition, alongside emerging approaches, including combination regimens, ctDNA-guided rechallenge, and genotype-specific inhibitors. Collectively, these insights highlight the evolving landscape of precision oncology in CRC and the importance of molecular stratification to optimize EGFR-targeted therapy and overcome resistance. Full article

Polygonatum odoratum, a medicinal and edible plant widely used in traditional Chinese medicine and daily diets, has potential in managing various disorders, but its anti-pruritic mechanisms remain unclear. This study aimed to explore its multi-target anti-pruritic effects by integrating network pharmacology, molecular docking, molecular dynamics (MD) simulations, GeneMANIA functional association analysis (GMFA), and GEO dataset validation. Bioactive components and pruritus-related targets were identified from public databases, and interaction networks between Polygonatum odoratum and pruritus targets, as well as the antihistamine levocetirizine, were constructed. Core targets were screened, and functional enrichment analyses were performed using DAVID and KEGG. Molecular docking (AutoDock Vina) and MD simulations (AMBER20) assessed the binding energy and stability of core components with key targets. The analysis identified 5 active components, 208 related targets, and 113 pruritus-associated targets, including 10 core targets. Enrichment analysis highlighted the PI3K/Akt and IL-17 signaling pathways, while MCODE clustering suggested involvement in arachidonic acid metabolism and serotonergic synapse. GMFA supported these findings. Molecular docking showed strong binding energy (<−5 kcal/mol), and MD simulations confirmed stable ligand–target complexes. GEO dataset validation reinforced key results. This study suggests that Polygonatum odoratum may exert anti-pruritic effects through the combined actions of inflammation suppression, skin barrier repair, and neural modulation, revealing a novel multi-target mechanism for pruritus therapy and potential synergy with levocetirizine. Full article

Background/Objectives: The medical mushroom Ophiocordyceps sinensis (Caterpillar Fungus), known for its ability to enhance “vitality,” is one of the most popular medicines in Asian traditional medical systems. According to the Chinese Pharmacopeia, O. sinensis is standardized for its adenosine content, the precursor of ATP, which mediates numerous physiological and pathological processes in many diseases. The related fungus of order Hypocreales, Cordyceps militaris, and its major bioactive constituents, 3′-deoxyadenosine (cordycepin), also exhibit pleiotropic biological activities. This review aims to provide a rationale for the adaptogenic and resilience-supporting effects of these medicinal fungi and to align food and drug regulation in Western countries. Methods: In this narrative review, we integrated results from chemical, pharmacokinetic, network pharmacology, preclinical, and clinical studies of O. sinensis, C. militaris, and cordycepin using network pharmacology and bioinformatics tools. Results: Across studies, recurrent mechanistic hubs included PI3K–Akt, AMPK–mTOR, MAPK, NF-κB, apoptosis, and adaptive stress-response signaling pathways, linking immune regulation and metabolic homeostasis. Experimental studies confirmed modulation of cytokine production, kinase signaling, and mitochondrial regulators. Clinical meta-analyses demonstrate consistent adjunctive benefits in renal and pulmonary disorders, although heterogeneity in preparation and methodological limitations remains significant. The review reveals controversy regarding the bioavailability of cordycepin in vivo and its concentration in vitro studies, raising the hypothesis that cordycepin may act as a driver, triggering the organism’s adaptive stress response in stress-induced and aging-related diseases. Pharmacokinetic data indicate that systemic cordycepin concentrations after oral administration remain in the nanomolar range, suggesting that some predicted molecular interactions may occur indirectly or through systems-level mechanisms. The review, for the first time, suggests establishing a regulatory category for resilience-supporting physiological modulators to align food and drug regulation in the EU with contemporary systems biology, thereby complementing the work of EFSA, EMA, FDA, and Asian authorities. Conclusions:O. sinensis, C. militaris, and 3-deoxyadenosine share a common adaptogenic mechanism for maintaining homeostasis of cellular and integrated biological system functions. The systems-level network analysis and reductionistic molecular ligand preceptor pharmacology provide complementary approaches for understanding the multi-target bioactivity of these fungi. This review clarifies conceptual and regulatory barriers to recognizing resilience-supporting interventions and informs future regulatory innovation. Full article

The progression of prostate cancer to castration-resistant disease (CRPC) remains a clinical challenge in which oxidative stress intersects with the PI3K/AKT–androgen receptor (AR) axis. Quercetin (QRC) is a redox-active dietary flavonol, yet its mechanistic impact on CRPC is incompletely defined. Here, we tested whether QRC suppresses AR output by directly modulating AKT. C4-2B and 22Rv1 CRPC cell lines were treated with increasing QRC concentrations, with or without enzalutamide (Enz). Proliferation and viability were monitored by IncuCyte imaging and SYTOX Green incorporation. AKT phosphorylation (S473), AR phosphorylation (S210/213), AR abundance and localization, and prostate-specific antigen (PSA) secretion were assessed by immunoblotting, immunofluorescence, and dot blot, respectively. Docking and molecular dynamic simulations were performed to identify and evaluate a putative QRC-binding site on AKT. QRC produced a dose-dependent cytostatic effect (IC₅₀ 24.37 μM in C4-2B; 21.54 μM in 22Rv1) without marked cell death, reduced pAKT(S473) by up to 80%, decreased pAR(S210/213), and diminished nuclear AR and PSA secretion. Simulations suggested a putative druggable allosteric pocket in the AKT1 N-lobe, with G159 emerging as a potential anchor residue. Enz cotreatment with QRC did not produce additive effects, consistent with a model in which QRC acts upstream of ligand-driven AR activation and thereby limits the incremental benefit of AR antagonism under these conditions. These data support QRC as an AKT–AR axis modulator in CRPC and provide a target engagement framework beyond simple ROS scavenging. Full article

For decades, the pharmacological identity of Panax ginseng has been primarily attributed to triterpenoid saponins known as ginsenosides. However, accumulating evidence indicates that ginseng also contains a structurally distinct lipid–protein complex, termed gintonin, enriched in lysophosphatidic acid (LPA) species. Unlike ginsenosides, which predominantly exert modulatory effects on membrane dynamics and intracellular kinase pathways, gintonin directly activates LPA G protein-coupled receptors (GPCRs), thereby inducing rapid phospholipase C (PLC) activation and intracellular Ca²⁺ mobilization. Biochemical analyses have identified major LPA species within the gintonin fraction, including C16:0, C18:0, and C18:1, stabilized within a proteinaceous matrix that may influence receptor engagement kinetics. Pharmacological studies demonstrate that gintonin preferentially activates LPA₁ and LPA₃ receptor subtypes, triggering downstream signaling cascades involving MAPK, PI3K/Akt, and Rho pathways. These receptor-mediated effects occur on a rapid temporal scale, distinguishing gintonin from the slower transcriptional and kinase-modulating actions of ginsenosides. In this review, we synthesize current evidence regarding the chemical architecture, receptor pharmacology, and signaling dynamics of gintonin and propose a dual signaling framework in which steroid-like saponins and lipid GPCR ligands represent complementary molecular axes within P. ginseng. Recognition of this layered signaling organization refines the molecular understanding of ginseng biology and highlights gintonin as a unique plant-derived GPCR ligand system. Full article

Programmed Death-Ligand 1 (PD-L1) promotes tumor progression through several mechanisms, including its intrinsic effect on breast cancer cell proliferation via the S-Phase Kinase-Associated Protein 2 (SKP2)–p21^Cip1/p27^Kip1 (SKP2-p21/p27) axis. However, the specific regulatory signaling through which PD-L1 influences the SKP2–p21/p27 axis to drive cell proliferation remains unclear. To investigate how PD-L1 mediates SKP2-dependent proliferation, proteomic analyses, gene-expression manipulation via knockdown or overexpression, Western blotting, quantitative immunofluorescence, colony-forming assays, real-time cell analysis, and Xenograft-derived cells were used. Proteomic data analysis identified several PD-L1 downstream targets as potential candidate regulators of the SKP2–p21/p27 axis and activators of the PI3K/AKT pathway. Candidate screening by gene knockdown, followed by analyses of SKP2, p21, and p27 protein expression, revealed Livin and Galectin-1 as upstream regulators of the SKP2–p21/p27 axis. Moreover, Western blotting and quantitative immunofluorescence in three breast cancer cell lines confirmed that PD-L1 is an upstream regulator of Livin, Galectin-1, and SKP2 protein expression. Mechanistically, Livin and Galectin-1 enhanced AKT phosphorylation (Ser473) to sustain PI3K/AKT pathway activation in a positive feedback loop to upregulate SKP2 expression. Functional assays, including colony-forming assays and real-time cell analyzer, demonstrated that Livin and Galectin-1 are critical for PD-L1-mediated, SKP2-dependent proliferation. These findings were corroborated in vivo using xenograft-derived cells. Overall, these findings delineate a tumor-intrinsic signaling axis in which PD-L1 upregulates Livin and Galectin-1 to sustain PI3K/AKT activity and drive SKP2-dependent cell proliferation. Targeting Livin and/or Galectin-1 may provide a rational strategy to disrupt PD-L1-associated proliferative signaling and improve combinatorial therapeutic approaches in breast cancer. Full article

There is no approved drug therapy for schwannomas associated with NF2-related schwannomatosis (NF2-SWN). Neither life-saving surgical resection or radiation are curative and can compound the debilitating neurological effects of the schwannomas. We previously identified fimepinostat, a dual histone deacetylase (HDAC)/phosphoinositide-3 kinase (PI3K) inhibitor, as a promising drug candidate with pro-apoptotic effects on NF2-related schwannomas. This preclinical study used the pharmaceutical formulation of fimepinostat to confirm its efficacy in schwannomas and identify pro-apoptotic signaling pathways. Fimepinostat was tested in human schwannoma model cells, patient-derived primary vestibular and non-vestibular schwannoma cells, and in a sciatic nerve allograft model. The signaling pathways leading to caspase-3-dependent apoptosis were elucidated using immune assays, flow cytometry, imaging, proteome, and acetylome analysis. Acute exposure to fimepinostat led to p21-dependent cell cycle inhibition, upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL R2), and downregulation of tumor necrosis factor receptor 1 (TNFR1), Yes-associated protein (YAP), and inhibitors of apoptosis. Moreover, fimepinostat downregulated cytokine and chemokine secretion increased by merlin loss in schwannoma cells. Fimepinostat is a promising new drug intervention for NF2-SWN patients with the potential to promote tumor regression. Full article

Alpha-2-macroglobulin (α₂M) is a conserved plasma glycoprotein traditionally known for its broad-spectrum protease inhibitory activity. However, emerging evidence indicates that its activated form, α₂M*, generated via proteolytic cleavage or nucleophilic attack, functions as a versatile signaling ligand. By engaging specific cell-surface receptors, most notably low-density lipoprotein receptor-related protein 1 (LRP1) and glucose-regulated protein 78 (GRP78), α₂M* orchestrates a diverse array of intracellular programs, including the PI3K/Akt/mTOR, MAPK/ERK, and JAK/STAT cascades, as well as mechanosensitive YAP/TAZ signaling. These pathways collectively govern fundamental cellular processes such as proliferation, metabolic reprogramming, cytoskeletal remodeling, and inflammatory adaptation across various cell types, including macrophages, cardiomyocytes, and malignant cells. Altogether, this review synthesizes current knowledge on α₂M activation, structural transitions, receptor interactions, and downstream signaling, highlighting the expanding functional landscape of α₂M* as a potent regulator of intracellular communication with implications for physiology and disease. Full article

Phytophthora infestans, a devastating oomycete pathogen responsible for late blight in solanaceous crops, relies on cellulose synthase (CesA) complexes for cell wall biosynthesis and virulence. Unlike plant CesAs that form homomeric trimers, oomycete CesA complexes are hypothesized to assemble as heteromeric units, yet their structural organization remains poorly defined. Here, we employed AlphaFold-Multimer and molecular docking to resolve the structural assembly of the PiCesA1–PiCesA2–PiCesA4 heterotrimer in P. infestans and identify potential ligand-binding sites for targeted inhibition. Structural modeling revealed a conserved transmembrane architecture combined with a distinctive cytosolic organization, in which N-terminal pleckstrin homology domains play a central role in heteromeric assembly. AlphaFold-Multimer consistently predicted a stable heterotrimer stabilized by cyclic interactions between pleckstrin homology domains and glycosyltransferase-A domains, forming an extensive interface network that is spatially segregated from the conserved UDP-glucose–binding catalytic core. Structure-guided docking identified potential ligands targeting pleckstrin homology–glycosyltransferase interface regions. Notably, these sites are absent or structurally divergent in plant cellulose synthases, underscoring their potential for pathogen-selective targeting. This work advances mechanistic understanding of cellulose biosynthesis in filamentous pathogens and proposes new avenues for selective disease control in agriculture. Full article

Oncometabolites and hypoxia-regulated exosomes orchestrate hypoxia-inducible factor (HIF)–driven macrophage reprogramming across chronic cardiometabolic and oncologic conditions. In type 2 diabetes (T2D) and obesity, regional hypoxia in expanding white adipose tissue (WAT) reconfigures macrophage immunometabolism and chemokine signaling, recruits C-C chemokine receptor 2 (CCR2⁺) monocytes, and skews adipose-tissue macrophages toward M1-like programs that sustain low-grade inflammation and blunt the physiological M1-to-M2 transition during wound repair. In atherosclerotic plaques, lipid-core hypoxia stabilizes HIF-1α, amplifies nuclear factor kappa-light-chain-enhancer of activated B cells/reactive oxygen species (NF-κB/ROS) signaling, increases matrix metalloproteinase-2/-9 (MMP-2/-9) release, and reduces ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux, weakening the fibrous cap. In tumors, poorly perfused niches accumulate lactate and succinate, which act as paracrine cues. Lactate activates PKA/cAMP pathways and promotes immunosuppressive tumor-associated macrophages (TAMs), whereas succinate signals through succinate receptor 1 (SUCNR1) to reinforce HIF-1α–dependent transcription and M2-like programming. In parallel, hypoxia-regulated exosomes deliver microRNAs such as miR-301a-3p, which suppress phosphatase and tensin homolog (PTEN) and activate PI3Kγ, thereby augmenting immunosuppression and programmed death-ligand 1 (PD-L1) expression. Clinically, this hypoxia–oncometabolite–exosome triad links oxygen debt with macrophage state, plaque destabilization, impaired wound repair, and tumor immune escape. Translational entry points include selective HIF-2α inhibition, phosphoinositide 3-kinase gamma (PI3Kγ) blockade, SUCNR1 targeting, and exosome-based miRNA modulation, while a biomarker panel comprising HIF-1α, vascular endothelial growth factor A (VEGF-A), and MMP-9 offers a pragmatic readout of hypoxia burden, macrophage programming, and therapeutic response. We conducted a focused narrative review (PubMed, Scopus, Web of Science; English; 2003–2025), prioritizing mechanistic and translational studies on hypoxia–HIF, lactate/succinate, and hypoxia-regulated exosomes across T2D, atherosclerosis, and cancer. Full article

The metallogelation process has been successfully achieved by utilizing a crystal engineering approach to generate a new metallogel. While the coordination of metal ions to ligands plays a very important role for building the primary structure, the stabilization and morphology of metallogels are heavily dependent on various intra-molecular interactions and non-covalent interactions, with hydrogen bonding (HB) often playing a dominant and structurally organizing role. In the present study, gelation experiments were achieved successfully by reacting vanadium acetylacetonate with a hydrazone ligand using different solvents. The metallogel shows excellent gelation ability with 1.7 wt% minimum gelator concentrations and the gel–sol dissociation temperature, T_gel is 55 °C (water/methanol). The structural properties of the metallogel were studied using single-crystal X-ray crystallography. The crystal structure analysis of the metallogel shows the presence of various interactions such as hydrogen bonding, pi–pi interactions, pnictogen bonding, and other weak non-covalent interactions. These molecular interactions play a very important role in the gelation process and also affect the gel’s properties like swelling behavior, viscosity, and elasticity. Full article

The aim of this study was to investigate the regulatory roles of distinct signaling cascades within the death receptor pathway in host cell apoptosis induced by Eimeria tenella (E. tenella); to this end, primary chicken embryo cecal epithelial cell culture, gene silencing, enzyme-linked immunosorbent assay (ELISA), Hoechst–Annexin V/PI apoptosis staining, hematoxylin–eosin (HE) staining, and quantitative real-time polymerase chain reaction (qRT-PCR) were employed. At 4, 24, 72, and 120 h post-inoculation (hpi) with E. tenella sporozoites, the proportion of apoptosis in six treatment groups [Group C, Group T0 (E. tenella infection group), Group T1 (E. tenella + Fas SiRNA), Group T2 (E. tenella + TRAIL SiRNA), Group T3 (E. tenella + TNFR1 SiRNA), and Group T4 (E. tenella + NC SiRNA)] and the dynamic changes in Fas cell surface death receptor (Fas), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), tumor necrosis factor receptor 1 (TNFR1), TNF receptor-associated death domain (TRADD), Fas-associated death domain (FADD), and death domain-associated protein (Daxx) expression and caspase-8 activity in the cells were determined. The results demonstrated that, from 4 to 120 hpi, the Fas and TNFR1 mRNA expression levels in Group T0’s host cells were significantly higher than those in Group C (p < 0.05 or p < 0.01). At 72 and 120 hpi, TRAIL mRNA expression in Group T0’s host cells was significantly or highly significantly elevated compared to that in Group C (p < 0.05 or p < 0.01). From 24 to 120 hpi, the expression levels of the FADD and Daxx genes, caspase-8 activity, and apoptotic rates in Group T1’s host cells were significantly lower than those in Group T4 (p < 0.05). At 72 and 120 hpi, the FADD expression, caspase-8 activity, and apoptotic rates in Group T2’s host cells were significantly reduced relative to Group T4 (p < 0.05). Additionally, at 4 hpi, TRADD gene expression in Group T3’s host cells was significantly lower than that in Group T4 (p < 0.05), while the apoptotic rate was significantly higher (p < 0.05). However, from 24 to 120 hpi, the TRADD expression, caspase-8 activity, and apoptotic rates in Group T3’s host cells were significantly lower than those in Group T4 (p < 0.05). The results indicated that, in the early stages of E. tenella development, TNFR1 overexpression promoted TRADD mRNA expression, thereby inhibiting the apoptosis of E. tenella host cells. In the middle and late developmental stages of E. tenella, the Fas-FADD, Fas-Daxx, TRAIL-FADD, and TNFR1-TRADD apoptotic pathways were all activated, collectively facilitating host cell apoptosis. The pro-apoptotic effects of these pathways were ranked in descending order, as follows: Fas signaling pathway > TNFR1 signaling pathway > TRAIL signaling pathway. Full article