Mechanism Of Activation Research Articles

Synergistic Catalysis of Cobalt Single Atoms and Clusters Loaded on Carbon Film: Enhancing Peroxymonosulfate Activation for Degradation of Norfloxacin

AbstractMany existing research focuses on the differences or performance comparisons between single‐atom or small‐sized nanocluster catalysts, but there is a lack of comprehensive research on the coupling relationship between the structure and activity and the mechanism of synergy. This study investigates the combined catalytic potential of cobalt single atoms (SAs) and nanoclusters (NCs) for enhanced peroxymonosulfate (PMS) activation to degrade norfloxacin (NFX). A novel CoSAs‐NCs/CN/TiO2 catalyst is synthesized, featuring cobalt SAs and NCs uniformly dispersed on the carbon film wrapping TiO2, and the degradation efficiency of the NFX solution is almost completely degraded, with a mineralization rate of 76.35%. Density functional theory (DFT) calculations indicate that the synergistic interaction between cobalt SAs and NCs promotes more efficient PMS adsorption and activation and significantly reduces the activation energy barrier, which enhances electron transfer and increases reactive oxygen species (ROS) generation. This research highlights the robust and versatile nature of this novel catalyst system in addressing various contaminants. This study elucidates the activation mechanism of catalysts, providing new ideas for advanced oxidation processes (AOPs) in environmental remediation, linking the structure and performance of catalysts, and emphasizes the practicality and importance of the CoSAs‐NCs/CN/TiO2 catalyst in effectively and long‐term remediation of water pollutants.

Deciphering Complement Activation Mechanisms in Childhood IgA Nephropathy

Deciphering Complement Activation Mechanisms in Childhood IgA Nephropathy

A threshold activation-based simplified Lv's transform algorithm for transient multi-component linear frequency modulation signals analysis.

The high sampling rate in modern digital systems generates a large scale of data. To address the computational burden, this paper proposes a threshold activation-based simplified Lv's transform (SLVT) algorithm to analyze the transient multi-component linear frequency modulation signals. Only the signal arrival can trigger the signal analysis. This mechanism alleviates the computation pressure because of the sparsity of signals. The threshold activation mechanism enables transient signal detection and sampling rate adjustment, thereby enhancing the efficiency and effectiveness of the analytical process. The simplified Lv's transform (LVT) removes redundant computations on stretch weighting and the Discrete Fourier Transform (DFT) in Lv's transform. SLVT uses the efficient Bluestein chirp-z algorithm to implement the stretch keystone transform. The comparison results show that SLVT reduces the computational complexity of the original LVT by at least 30.8%. This algorithm exhibits superior performance compared to other advanced signal processing methods, such as discrete chirp Fourier transform, fractional Fourier transform, and Radon Wigner transform algorithms, in terms of parameter extraction accuracy, computational complexity, and execution time. Moreover, the implementation of a field programmable gate array accelerates SLVT computing by a factor of 116 in comparison to the CPU (Central Processing Unit) platform.

Effective activation of PMS by encapsulating monodispersed Fe3O4 within N, S heteroatoms co-doped carbon chamber for ROX removal dominated by the non-radical pathway

Developing the eco-friendly catalyst-adsorption iron-based materials with improved catalytic activity and minimal Fe leaching is fascinating for roxarsone (ROX) removal. Herein, Fe3O4 nanoparticles were encapsulated in flexible N, S-modified carbon chamber (Fe3O4@NS4C) through the “hydrothermal + pyrolysis” process to form a catalyst with multi-active sites. ROX could be degraded nearly 100 % at pH 5.0 − 11.0 and secondary inorganic As species concentration is lower than 0.09 mg/L by efficient adsorption. Especially, the Fe ion leaching concentration in Fe3O4@NS4C/PMS after ROX removal is decreased to 0.08 mg/L. Combined with quenching experiment, EPR, Raman spectroscopy and electrochemical analysis, the non-radical activation mechanism dominated by 1O2 and electron transfer was determined. The synergistic interaction between the N doped sites and the S anchored sites within the carbon matrix not only improves the adsorption of PMS on the catalyst but also facilitates the direct activation of PMS to 1O2, while the surface electron transfer improves the Fe2+/Fe3+ redox cycling in PMS activation. The active sites of ROX attacked by 1O2 were examined through Fukui function computations. Combined with HPLC-MS, the ROX degradation pathway was determined, and the toxicity of intermediates was evaluated. Furthermore, the removal performance of ROX in Fe3O4@NS4C/PMS system was also assessed in different environment for practical application, indicating that the advantages in the synergy between N, S co-doping carbon chamber and encapsulated iron oxide for water purification.

The role of the immune response in developing tuberculosis infection: from latent infection to active tuberculosis

Despite advancements in modern medicine, tuberculosis continues to be one of the leading causes of death globally. Findings indicate that COVID-19 may trigger the activation of tuberculosis infection (TB), leading to its spread. Despite the development of new immunological diagnostic methods for latent tuberculosis infection (LTBI), it is still unclear how the infection transitions to an active TB state. The goal of the study is to provide insights into the progression of tuberculosis infection from a latent to an active state. This article presents recent research data focused on investigating the pathogenesis of LTBI, particularly the immune responses in the interaction between Mycobacteria tuberculosis (Mtb) and the host. It describes the mechanisms of T-cell immunity and cytokine activation, supporting the concept of type 1, type 2, and type 3 immune responses. According to the conducted studies, Th17 cells have a significant role in the development of type 3 antigen-specific responses. The cytokines IL-6 and IL-23 activate STAT3, which is necessary to trigger the expression of Th17. Future research on the role of Th17 cells and cytokines, particularly IL-6 and IL-21, may be beneficial in understanding the shift from LTBI to active TB.

Preferred Electric Field Mechanism for Frustrated Lewis Pair Reactivity.

This study employs computational methods to investigate the mechanism of H2 activation by frustrated Lewis pair (FLP) species, including both intermolecular and intramolecular nitrothane/borane FLP systems. Previous studies have proposed two qualitative reactivity mechanism models to explain the facile cleavage of H2 by FLPs. The findings of this study support the electric field mechanism as the favorable pathway for H2 cleavage. Utilizing frontier molecular orbital theory and energy decomposition analysis, the study explores the electronic structure and nature of the reactions under an external electric field (EEF). Analysis using the activation strain model highlights the significant influence of geometrical deformation energies of FLPs on the activation barriers of H2 activation reactions. Computational results suggest that H2 activation by FLP molecules follows the electric field mechanism, indicating the potential of the FLP/EEF combination as an effective activator for inert molecules.

Capturing Autoinhibited PDK1 Reveals the Linker's Regulatory Role, Informing Innovative Inhibitor Design.

PDK1 is crucial for PI3K/AKT/mTOR and Ras/MAPK cancer signaling. It phosphorylates AKT in a PIP3-dependent but S6K, SGK, and RSK kinases in a PIP3-independent manner. Unlike its substrates, its autoinhibited monomeric state has been unclear, likely due to its low population time, and phosphorylation in the absence of PIP3 has been puzzling too. Here, guided by experimental data, we constructed models and performed all-atom molecular dynamics simulations. In the autoinhibited PDK1 conformation that resembles autoinhibited AKT, binding of the linker between the kinase and PH domains to the PIF-binding pocket promotes the formation of the Glu130-Lys111 salt bridge and weakens the association of the kinase domain with the PH domain, shifting the population from the autoinhibited state to states accessible to the membrane and its kinase substrates. The interaction of the substrates' hydrophobic motif and the PDK1 PIF-binding pocket facilitates the release of the autoinhibition even in the absence of PIP3. Phosphorylation of the serine-rich motif within the linker further attenuates the association of the PH domain with the kinase domain. These suggest that while the monomeric autoinhibited state is relatively stable, it can readily shift to its active, catalysis-prone state to phosphorylate its diverse substrates. Our findings reveal the PDK1 activation mechanism and discover the regulatory role of PDK1's linker, which lead to two innovative linker-based inhibitor strategies: (i) locking the autoinhibited PDK1 through optimization of the interactions of AKT inhibitors with the PH domain of PDK1 and (ii) analogs (small molecules or peptidomimetics) that mimic the linker interactions with the PIF-binding pocket.

Insight into the nonradical selective oxidation mechanism for versatile organic pollutants removal by perovskite activated peroxymonosulfate system

The heterogeneous catalysis of peroxymonosulfate (PMS) through nonradical pathway has shown many advantages in environmental remediation. It is necessary to unveil the factors affecting oxidation routes and selectivity toward different organic pollutants. Herein, a series of ABO3-type BiFexCo1-xO3 perovskite catalysts were fabricated via simple hydrothermal process to realize the changeover of catalytic activity and mechanism in PMS activation and pollutants oxidation. The as-prepared BiFe0.5Co0.5O3 (BFCO-3) achieved a 98 % removal efficiency of SMZ with a high kinetic constant (kobs = 0.334 min−1) in 10 min. The superior catalytic performance was ascribed to the introduction of bimetals at B-site, which enhanced electron donating capacity to PMS, confirming by d-band center calculations. Several parameters such as inorganic anions and humic acids affected the SMZ degradation slightly, owing that singlet oxygen was verified to be the primary reactive species in the BFCO-3/PMS system. Moreover, twelve organic pollutants including amoxicillin crystalline (AMX), cephalexin hydrate (CFX), ciprofloxacin (CIP), levofloxacin (LFX), Sulfadiazine (SDZ), sulfamethoxazole (SMZ), 4-acetamidophenol (ACP), benzoic acid (BA), bisphenol A (BPA), carbamazepine (CBZ), metronidazole (MNZ) and naproxen (NPX) were utilized to investigate the selective oxidation mechanism. A linear correlation between lnkobs and their half-wave potential (φ1/2) values (except for BA and MNZ) suggesting the dominant role of nonradical catalysis where phenolic compounds with lower anodic potential tend to lose electrons are more easily degraded. Furthermore, the reactive sites of representative SMZ for electrophilic species attack were precisely identified based on the Fukui index. And the degradation intermediates of SMZ were further determined by LC-MS/MS technology for proposing their degradation pathway and predicting ecotoxicity. This study not only provides an efficient advanced oxidation system for organic pollutants removal but also advances our understanding of the selective oxidation mechanism in nonradical-dominated catalytic process.

A novel dual-detection electrochemiluminescence sensor for the selective detection of Hg2⁺ and Zn2⁺: Signal suppression and activation mechanisms

In this study, we developed a novel covalent organic framework (COF) material, termed RuCOFs, specifically designed and synthesized for electrochemiluminescence (ECL) sensor applications. RuCOFs are based on the classic ECL emitter Ru(dcbpy)32+, ingeniously integrating 4,4′,4''-(1,3,5-triazine-2,4,6-triyl) triphenylamine (TAPT) with [2,2′-bipyridine]-5,5′-diamine (BPYDA), forming a structure with a high specific surface area. This configuration not only significantly enhances the stability of the ECL signal but also provides ideal N,N′-bipyridine chelating sites for efficient metal ion recognition. Utilizing Ru(dcbpy)32+-functionalized COF (RuCOFs), a novel dual-function ECL sensor was developed, achieving high sensitivity and selectivity in detecting mercury (Hg2⁺) and zinc (Zn2⁺) ions. Experimental results indicate that Hg2⁺ significantly quenches the ECL signal, while Zn2⁺ markedly enhances it, with detection limits of 4.71 nM for Hg2⁺ and 6.57 nM for Zn2⁺ across a wide linear response range from 1 μM to 1 nM. This research not only demonstrates the significant advantages of COF-based ECL sensing platforms in tracking environmental metal ions but also opens new possibilities for environmental monitoring.

Novel insight into mechanisms of ROS1 catalytic activation via loss of the extracellular domain.

The ROS1 receptor tyrosine kinase (RTK) possesses the largest extracellular amino-terminal domain (ECD) among the human RTK family, yet the mechanisms regulating its activation are not fully understood. While chimeric ROS1 fusion proteins, resulting from chromosomal rearrangements, are well-known oncogenic drivers, their activation mechanisms also remain underexplored. To elucidate the role of the ROS1 ECD in catalytic regulation, we engineered a series of amino-terminal deletion mutants. Our functional studies compared the full-length ROS1 receptor, the CD74-ROS1 oncogenic fusion, and ECD-deleted ROS1 constructs, identifying the ECD regions that inhibit ROS1 tyrosine kinase activity. Notably, we found that deletion of the ROS1 ECD alone significantly increases constitutive catalytic activation and neoplastic transformation in the absence of an amino-terminal fusion partner, challenging the presumed necessity for a dimerization domain in the activation mechanism of kinase fusions in cancer. Our data suggest that inter-genic deletions resulting in the loss of the ECD may be underappreciated oncogenic drivers in cancer. Furthermore, our studies demonstrate that RNASE7 is not a ligand for the ROS1 receptor as previously reported, confirming that ROS1 remains an orphan receptor. Thus, the discovery of a ROS1 ligand remains an important future priority. These findings highlight the potential for disease-associated somatic aberrations or splice variants that modify the ROS1 ECD to promote constitutive receptor activation, warranting further investigation.

Cryo-EM structure of small-molecule agonist bound delta opioid receptor-Gi complex enables discovery of biased compound

Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low risk of drug dependence. Despite its potential applications, the pharmacological properties of δOR, including the mechanisms of activation by small-molecule agonists and the complex signaling pathways it engages, as well as their relation to the potential side effects, remain poorly understood. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-Gi complex when bound to a small-molecule agonist (ADL5859). Moreover, we design a series of probes to examine the key receptor-ligand interaction site and identify a region involved in signaling bias. Using ADL06 as a chemical tool, we elucidate the relationship between the β-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the β-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR’s structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery.

Task decomposition strategy based on machine learning for boosting performance and identifying mechanisms in heterogeneous activation of peracetic acid process

Heterogeneous activation of peracetic acid (PAA) process is a promising method for removing organic pollutants from water. Nevertheless, this process is constrained by several complex factors, such as the selection of catalysts, optimization of reaction conditions, and identification of mechanism. In this study, a task decomposition strategy was adopted by combining a catalyst and reaction condition optimization machine learning (CRCO-ML) model and a mechanism identification machine learning (MI-ML) model to address these issues. The Categorical Boosting (CatBoost) model was identified as the best-performing model for the dataset (1024 sets and 7122 data points) in this study, achieving an R2 of 0.92 and an RMSE of 1.28. Catalyst composition, PAA dosage, and catalyst dosage were identified as the three most important features through SHAP analysis in the CRCO-ML model. The HCO3– is considered the most influential water matrix affecting the k value. The errors between all reverse experiment results and the predictions of the CRCO-ML and MI-ML models were <10 % and 15 %, respectively. This interdisciplinary work provides novel insights into the design and application of the heterogeneous activation of PAA process, significantly contributing to the rapid development of this technology.

Focal deletions of a promoter tether activate the IRX3 oncogene in T-cell acute lymphoblastic leukemia

AbstractOncogenes can be activated in cis through multiple mechanisms including enhancer hijacking events and noncoding mutations that create enhancers or promoters de novo. These paradigms have helped parse somatic variation of noncoding cancer genomes, thereby providing a rationale to identify noncanonical mechanisms of gene activation. Here we describe a novel mechanism of oncogene activation whereby focal copy number loss of an intronic element within the FTO gene leads to aberrant expression of IRX3, an oncogene in T-cell acute lymphoblastic leukemia. Loss of this CTCF-bound element downstream to IRX3 (+224 kb) leads to enhancer hijack of an upstream developmentally active super-enhancer of the CRNDE long noncoding RNA (−644 kb). Unexpectedly, the CRNDE super-enhancer interacts with the IRX3 promoter with no transcriptional output until it is untethered from the FTO intronic site. We propose that “promoter tethering” of oncogenes to inert regions of the genome is a previously unappreciated biological mechanism preventing tumorigenesis.

Tuning RXR Modulators for PGC1α Recruitment.

The molecular activation mechanism of the nuclear retinoid X receptors (RXRs) crucially involves ligand-induced corepressor release and coactivator recruitment which mediate transcriptional repression or activation. The ability of RXR to bind diverse coactivators suggests that a coregulator-selective modulation by ligands may open an avenue to tissue- or gene-selective RXR activation. Here, we identified strong induction of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) binding to RXR by a synthetic agonist but not by the endogenous ligand 9-cis retinoic acid. Structure-guided diversification of this lead resulted in a set of three structurally related RXR agonists with different ability to promote PGC1α recruitment in cell-free and cellular context. These results demonstrate that selective modulation of coregulator recruitment to RXR can be achieved with molecular glues and potentially open new therapeutic opportunities by targeting the ligand-induced RXR-PGC1α interaction.

Enhancing T-cell recruitment in renal cell carcinoma with cytokine-armed adenoviruses

ABSTRACT Immunotherapy has emerged as a promising approach for cancer treatment, with oncolytic adenoviruses showing power as immunotherapeutic agents. In this study, we investigated the immunotherapeutic potential of an adenovirus construct expressing CXCL9, CXCL10, or IL-15 in clear cell renal cell carcinoma (ccRCC) tumor models. Our results demonstrated robust cytokine secretion upon viral treatment, suggesting effective transgene expression. Subsequent analysis using resistance-based transwell migration and microfluidic chip assays demonstrated increased T-cell migration in response to chemokine secretion by infected cells in both 2D and 3D cell models. Flow cytometry analysis revealed CXCR3 receptor expression across T-cell subsets, with the highest percentage found on CD8+ T-cells, underscoring their key role in immune cell migration. Alongside T-cells, we also detected NK-cells in the tumors of immunocompromised mice treated with cytokine-encoding adenoviruses. Furthermore, we identified potential immunogenic antigens that may enhance the efficacy and specificity of our armed oncolytic adenoviruses in ccRCC. Overall, our findings using ccRCC cell line, in vivo humanized mice, physiologically relevant PDCs in 2D and patient-derived organoids (PDOs) in 3D suggest that chemokine-armed adenoviruses hold promise for enhancing T-cell migration and improving immunotherapy outcomes in ccRCC. Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC.

Copper-Catalyzed Enantioselective [4π + 2σ] Cycloaddition of Bicyclobutanes with Nitrones.

The selective construction of bridged bicyclic scaffolds has garnered increasing attention because of their extensive use as saturated bioisosteres of arene in pharmaceutical industry. However, in sharp contrast to their racemic counterparts, assembling chiral bridged bicyclic structures in an enantioselective and regioselective manner remains challenging. Herein, we describe our protocol for constructing chiral 2-oxa-3-azabicyclo[3.1.1]heptanes (BCHeps) by enantioselective [4π + 2σ] cycloadditions of bicyclo[1.1.0]butanes (BCBs) and nitrones taking advantage of a chiral copper(II) complex as a Lewis acid catalyst. This method features mild conditions, good functional group tolerance, high yield (up to 99%), and excellent enantioselectivity (up to 99% ee). Density functional theory (DFT) calculation elucidates the origin of the reaction's enantioselectivity and the mechanism of BCB activation by Cu(II) complex.

Structural insights into the molecular recognition of integrin αVβ3 by RGD-containing ligands: The role of the specificity-determining loop (SDL).

Integrin αVβ3 is a prominent member of the "RGD-recognizing" integrin family of cell surface receptors. αVβ3 binds to various extracellular matrix (ECM) proteins and oxysterols such as 25-hydroxycholesterol, is implicated in several diseases, including cancer metastasis, lung fibrosis, inflammation, and autoimmune diseases, and is pursued as a valuable therapeutic target. Despite enormous efforts to seek a pure antagonist, to date, no single drug candidate has successfully reached clinics due to associated partial agonism and toxicity issues. Developing effective and safe inhibitors require a thorough understanding of the molecular interactions and structural changes related to the receptor's activation and inhibition mechanisms. This study offers a comprehensive residue-residue contact and network analyses of the ligand-binding β-propeller βI domains (headpiece) based on all available experimental structures of integrin αVβ3 in unliganded, agonist-, antagonist-, and antibody-bound states. The analyses reveal many critical interactions that were not reported before and show that specific orientation and interactions of residues from the specificity-determining loop (SDL) are critical in molecular recognition and regulation. Also, the network analysis reveals that residues from the nearby allosteric site (site II) connect to the primary RGD-binding site via SDL, which likely acts as an interface between the two sites. Our results provide valuable insights into molecular interactions, structural changes, distinct features of the active and inactive headpiece conformations, the role of SDL in ligand recognition, and SDL-mediated allostery. Thus, the insights from this study may facilitate the designing of pure antagonists or site II-mediated allosteric modulators to integrin αVβ3 to treat various diseases.

Hydroxylamine hydrochloride-driven activation of NiFe2O4 for the degradation of phenol via peroxymonosulfate

In this study, hydroxylamine hydrochloride (HA) was employed to enhance the activation of NiFe2O4 towards peroxymonosulfate (PMS) for the effective degradation of phenol. NiFe2O4 particles were synthesized via a simple hydrothermal method, followed by characterization of their surface morphology, and microstructure. Upon the addition of HA to the system of NiFe2O4/PMS, the degradation activity is significantly enhanced. The degradation efficiency of phenol reached 98.5% after 60 min using 0.6 g/L NiFe2O4, 3 mmol/L PMS, 2 mmol/L HA at pH 7, which increased by 4.76 times compared to the system without HA. The study further explored the activation mechanism of the NiFe2O4/HA/PMS system, revealing that HA significantly enhanced the conversion of Fe3+/Fe2+ and the leaching of metal ions, thereby accelerating the reaction rate. In addition, the NiFe2O4/HA/PMS system proved effective across a broad range of pH values. This study provides new insights and perspectives into enhancing peroxymonosulfate activation coupled with metal oxides catalysts through the use of reducing agents.

Plant-Derived Flavonoids as AMPK Activators: Unveiling Their Potential in Type 2 Diabetes Management through Mechanistic Insights, Docking Studies, and Pharmacokinetics

Type 2 diabetes mellitus (T2DM) remains a significant global health issue, marked by insulin resistance and disrupted glucose metabolism. AMP-activated protein kinase (AMPK) serves as a key regulator of cellular energy balance, playing a crucial role in enhancing insulin sensitivity, promoting glucose uptake, and reducing glucose production in the liver. Recently, there has been growing interest in plant-derived flavonoids as natural activators of AMPK, offering a promising complementary approach to conventional diabetes treatments. This review delves into ten flavonoids identified as AMPK activators, including baicalein, dihydromyricetin, bavachin, 7-O-MA, derrone, and alpinumisoflavone. Their activation mechanisms are explored, which include both direct binding to the AMPK complex and indirect pathways involving upstream signaling. Through molecular docking studies, the binding affinities and interaction profiles of these flavonoids with AMPK are assessed, revealing varying levels of activation potential. Notably, baicalein and dihydromyricetin showed strong binding to the α1 subunit of AMPK, indicating high potential for robust activation. Additionally, this review provides a thorough analysis of the pharmacokinetic properties and drug-likeness of these flavonoids using the SwissADME tool, focusing on aspects such as ADME (Absorption, Distribution, Metabolism, and Excretion). While the overall profiles of these compounds are promising, issues like solubility and possible drug–drug interactions are areas that need further refinement. In summary, plant-derived flavonoids emerge as a promising avenue for developing new natural therapies for T2DM. Moving forward, research should aim at optimizing these compounds for clinical application, elucidating their specific mechanisms of AMPK activation, and confirming their efficacy in T2DM treatment. This review highlights the potential of flavonoids as safer and more holistic alternatives or adjuncts to current diabetes therapies.

Study on the Mechanism of FOXA2 Activation on Glutathione Metabolic Reprogramming Mediated by ETV4 Transcription to Facilitate Colorectal Cancer Malignant Progression.

The metabolic imbalance of glutathione (GSH) has been widely recognized in most cancers, but the specific molecular mechanism of GSH metabolic regulation in the malignant progression of colorectal cancer (CRC) is unexplored. The objective of our project is to elucidate whether ETV4 affects the malignant progression of CRC through GSH metabolic reprogramming. Bioinformatics and molecular experiments measured the expression of ETV4 in CRC, and in vitro experiments explored the impact of ETV4 on CRC malignant progression. The Kyoto Encyclopedia of Genes and Genomes (KEGG) identified the pathway of ETV4 enrichment. The bioinformatics approach identified FOXA2 as an upstream regulatory factor of ETV4. The dual-luciferase assay, chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) experiment verified the binding relationship between ETV4 and FOXA2. Cell viability, migration, and invasion abilities were determined by conducting CCK-8, wound healing, and Transwell assays, respectively. The expression levels of N-cadherin, E-cadherin, and vimentin were determined by utilizing immunofluorescence (IF). Metabolism-related enzymes GCLM, GCLC, and GSTP1 levels were detected to evaluate the GSH metabolism level by analyzing the GSH/GSSG ratio. In vivo experiments were performed to explore the effect of FOXA2/ETV4 on CRC progression, and the expression of related proteins was detected by western blot. ETV4 was highly expressed in CRC. Knocking down ETV4 suppressed CRC cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT) progression in vitro. ETV4 was abundant in the GSH metabolic pathway, and overexpression of ETV4 facilitated CRC malignant progression through activation of the GSH metabolism. In addition, in vitro cellular experiments and in vivo experiments in nude mice confirmed that FOXA2 transcriptionally activated ETV4. Knocking down FOXA2 repressed the malignant phenotype of CRC cells by suppressing GSH metabolism. These effects were reversed by overexpressing ETV4. Our results indicated that FOXA2 transcriptionally activates ETV4 to facilitate CRC malignant progression by modulating the GSH metabolic pathway. Targeting the FOXA2/ETV4 axis or GSH metabolism may be an effective approach for CRC treatment.