SEARCH · Search PubMed

Results for “Hypoxia-Inducible Factor 1, alpha Subunit”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

14 recordsLinked to original sources

PubMed2025

Exploration of the mechanism of the Mongolian medicine Tonglaga-5 (-5) for the treatment of n-methyl-n'-nitro-n-nitrosoguanidine-induced chronic atrophic gastritis based on network pharmacology and metabolomics.

OBJECTIVE: To explore the mechanism of Tonglaga-5 (-5, TLG-5) for the treatment of chronic atrophic gastritis (CAG), based on network pharmacology and metabolomics. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into six groups (n = 8): control group; model group; teprenone group, and low-, median-, and high- dose TLG-5 groups. The enzyme linked immunosorbent assay (ELISA) was used to measure the expression of pepsinogen Ⅰ (PG Ⅰ), pepsinogen Ⅱ (PG Ⅱ) and gastrin-17 (G-17) in the serum. Hematoxylin and eosin staining were performed to observe the pathological condition. And the network pharmacology was employed to identify the targets and signaling pathways of TLG-5 affecting CAG. Then, the metabolomics approach was applied to explore the specific metabolites and metabolic pathways. Finally, validation was performed using the "metabolite-gene" interaction network, molecular docking and quantitative real-time polymerase chain reaction (qPCR). RESULTS: High-dose TLG-5 significantly improved the expression of PG Ⅰ, PGR (PG Ⅰ/ PG Ⅱ) and G-17 (P < 0.05) and inhibited the expression of phosphoinositide-3-kinase regulatory subunit 2, AKT serine/threonine kinase (AKT), hypoxia-inducible factor 1-alpha (HIF-1α) (P < 0.05). Further, high-dose TLG-5 reduced the number of glands was reduced, and fibrosis with oedema and ecchymosis appeared at the base. Overlapping TLG-5 and CAG gene targets produced 270 interactive targets. The results of gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses suggested that TLG-5 could affect CAG through the predominantly cancer and inflammation-related pathways. Pyrimidine metabolism was identified as a significantly differential pathway in the mechanism of TLG-5 for treating CAG. CONCLUSIONS: TLG-5 exerts a therapeutic effect on CAG by regulating β-alanine metabolism, pyrimidine metabolism pathways, and inhibiting the PI3K-AKT signaling pathway and HIF-1 signaling pathways.

Animals↗

PubMed2004

Hepatocyte growth factor-activated NF-kappaB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines.

Hepatocyte growth factor (HGF)-stimulated Met signaling influences tumor survival, growth and progression, all processes involving the transcription factor NF-kappaB. NF-kappaB plays a complex role in the control of survival due to the influence of cellular factors acting downstream. We undertook a comparative investigation of two human breast carcinoma cells with different grades of malignancy and HepG2 hepatoma cells, which present a biphasic response to HGF (proliferation followed by apoptosis). We found evidence that HGF induced gene patterns characteristic of survival rather than apoptosis depending on the cell type. The ability of NF-kappaB to regulate expression of hypoxia-inducible factor-1alpha (HIF-1alpha), a survival/anti-apoptotic gene in cancer, seemed to be critical. In the HepG2 and MCF-7 (low invasive breast carcinoma) cell lines increased transcription and translation were responsible for HIF-1alpha induction after HGF. The regulation by NF-kappaB was mainly at the level of the 5'-UTR of the HIF-1alpha message. HIF-1 (alpha/beta heterodimer) was likely to transactivate Mcl-1, another anti-apoptotic gene. Opposite results were observed in MDA-MB-231 cells (highly invasive breast carcinoma), which have high NF-kappaB activity, further inducible by HGF, because HIF-1alpha mRNA expression and HIF-1 transactivating capacity were HGF-insensitive while the alpha subunit seemed to be degraded after HGF. However, ornithine decarboxylase (ODC) and heme oxygenase mRNA expression persistently increased. By transiently transfecting two ODC gene reporters we demonstrated that ODC is a target gene of NF-kappaB in HGF-treated tumor cells. By regulating HIF-1 activity and specific gene expression downstream, NF-kappaB may influence the survival threshold, with an impact on the fate of carcinoma cells after prolonged HGF treatment.

Breast Neoplasms↗

PubMed2001

Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation.

Oxygen-dependent proteolytic destruction of hypoxia-inducible factor-alpha (HIF-alpha) subunits plays a central role in regulating transcriptional responses to hypoxia. Recent studies have defined a key function for the von Hippel-Lindau tumour suppressor E3 ubiquitin ligase (VHLE3) in this process, and have defined an interaction with HIF-1 alpha that is regulated by prolyl hydroxylation. Here we show that two independent regions within the HIF-alpha oxygen-dependent degradation domain (ODDD) are targeted for ubiquitylation by VHLE3 in a manner dependent upon prolyl hydroxylation. In a series of in vitro and in vivo assays, we demonstrate the independent and non-redundant operation of each site in regulation of the HIF system. Both sites contain a common core motif, but differ both in overall sequence and in the conditions under which they bind to the VHLE3 ligase complex. The definition of two independent destruction domains implicates a more complex system of pVHL-HIF-alpha interactions, but reinforces the role of prolyl hydroxylation as an oxygen-dependent destruction signal.

Amino Acid Motifs↗

PubMed2025

Annexin A2 binds the 3'-UTR of H2AX mRNA and regulates histone-H2AX-derived hypoxia-inducible factor 1-alpha activation.

Annexin A2 (Anxa2), a multifunctional protein with RNA-binding capabilities, is frequently overexpressed in various tumors, and its expression is highly correlated with malignant progression. In this study, we demonstrate for the first time that Anxa2 was co-expressed with glycolytic genes, suggesting its potential role as a regulator of glycolysis. RNA-protein interaction assay revealed that Anxa2 interacted with 3'-UTR of H2AX mRNA and protected it from miRNA-mediated degradation. Up-regulated Histone-H2AX enhances the expression of glycolytic genes including GLUT1, HK2, PGK1, ENO1, PKM2, GAPDH and LDHA via stabilizing hypoxia-inducible factor 1-alpha (HIF1α), thereby accelerating lactic acid production and secretion. (20S) G-Rh2, a natural compound targeting Anxa2, significantly interfered the Anxa2-H2AX mRNA interaction, and inhibited subsequent glycolysis progression. We propose that Anxa2 acts as a novel regulator in glycolysis via enhancing H2AX expression, and (20S) G-Rh2 may exert its anti-cancer activity by targeting Anxa2-H2AX-HIF1α-glycolysis axis in human hepatoma HepG2 cells.

Humans↗

PubMed2018

E3 Ligase VHL Promotes Group 2 Innate Lymphoid Cell Maturation and Function via Glycolysis Inhibition and Induction of Interleukin-33 Receptor.

Group 2 innate lymphoid cells (ILC2s) are a specialized subset of lymphoid effector cells that are critically involved in allergic responses; however, the mechanisms of their regulation remain unclear. We report that conditional deletion of the E3 ubiquitin ligase VHL in innate lymphoid progenitors minimally affected early-stage bone marrow ILC2s but caused a selective and intrinsic decrease in mature ILC2 numbers in peripheral non-lymphoid tissues, resulting in reduced type 2 immune responses. VHL deficiency caused the accumulation of hypoxia-inducible factor 1α (HIF1α) and attenuated interleukin-33 (IL-33) receptor ST2 expression, which was rectified by HIF1α ablation or inhibition. HIF1α-driven expression of the glycolytic enzyme pyruvate kinase M2 downmodulated ST2 expression via epigenetic modification and inhibited IL-33-induced ILC2 development. Our study indicates that the VHL-HIF-glycolysis axis is essential for the late-stage maturation and function of ILC2s via targeting IL-33-ST2 pathway.

Animals↗

PubMed2026

Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.

High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.

Ferroptosis↗

PubMed2026

Dynamic transcriptomic landscape from bulk RNA-seq reveals critical mmu-miR-181a-5p/hif1a and mmu-miR-101a-3p/col1a1 modules for deep second-degree burn wound healing.

Burn injuries constitute a significant global health challenge, with deep partial-thickness burns (deep second-degree) posing particular clinical concerns due to prolonged healing and high scarring risks stemming from reticular dermis damage. Current therapeutic strategies remain largely empirical, reflecting limited understanding of stage-specific regulatory mechanisms. This study systematically investigated the molecular basis of deep partial-thickness burn repair by establishing murine models and performing RNA-seq analysis across healing phases (0, 3, 7, 14 days post-burn, dpb). Integrated bioinformatics revealed pivotal ceRNA and PPI networks, identifying hif1a (hypoxia-responsive immunomodulator) and col1a1 (ECM remodeling hub) as nodal regulators. Mechanistically, mmu-miR-101a-3p and mmu-miR-181a-5p were validated as post-transcriptional repressors of col1a1 and hif1a, respectively. Our work pioneers the discovery of the mmu-miR-181a-5p/hif1a and mmu-miR-101a-3p/col1a1 axes as master regulators of burn repair, offering novel therapeutic targets. The multi-omics dataset and molecular networks established herein provide a foundational resource for wound healing research.

MicroRNAs↗

PubMed2026

Unbiased screen of human transcriptome reveals an unexpected role of 3'UTRs in translation initiation.

Although most eukaryotic mRNAs require a 5'-cap for translation initiation, some can also be translated through a poorly studied cap-independent pathway. Here we develop a circRNA-based system and unbiasedly identify more than 10,000 sequences in the human transcriptome that contain Cap-independent Translation Initiators (CiTIs). Surprisingly, most of the identified CiTIs are located in 3'UTRs, which mainly promote translation initiation in mRNAs bearing highly structured 5'UTR. Mechanistically, CiTI recruits several translation initiation factors including eIF3 and DHX29, which in turn unwind 5'UTR structures and facilitate ribosome scanning. Functionally, we show that the translation of HIF1A mRNA, an endogenous DHX29 target, is antagonistically regulated by its 5'UTR structure and a new 3'-CiTI in response to hypoxia. Consistently, deletion of 3'-CiTI suppresses cell growth in hypoxia and tumor progression in vivo. Collectively, our study uncovers a new regulatory mode for translation where the 3'UTR actively participate in the translation initiation.

Humans↗

PubMed2025

Retinal hypoxia reversal with PLGA-oxygen nanobubbles.

Pathologies associated with retinal hypoxia, including diabetic retinopathy, central/branch retinal artery occlusion (CRAO/BRAO), central/branch retinal vein occlusion (CRVO/BRVO), retinopathy of prematurity, sickle cell retinopathy, etc., have limited effective therapeutic intervention strategies. To address this shortcoming, herein we propose a biocompatible and biodegradable poly (lactic-co-glycolic acid) shell-based oxygen nanobubbles (PLGA-ONBs) platform, formulated with PLGA, polyvinyl alcohol (PVA), and NaHCO3. The formulation of a novel PLGA-ONBs was proposed, and the synthesis process was optimized with respect to dependent (sonication power, PVA, and NaHCO3 concentrations) and response (hydrodynamic diameter and oxygen capacity) variables. The optimized formulation has a concentration of (13.8 ± 0.01) × 1010 particles per ml with a hydrodynamic diameter of 142.83 ± 11.46 nm, and oxygen loading capacity of 47.2 ± 2.4 mg L-1. After 4 weeks of storage, the ONBs were found to have an oxygen concentration of 38.9 ± 2.9 mg L-1, indicating excellent oxygen retention capability. The PLGA-ONBs tested in vitro in Muller and R28 retinal cell lines demonstrated excellent biocompatibility and potential to mitigate hypoxia. In addition, the PLGA-ONBs treatment on hypoxic cells demonstrated restoration of mRNA expression of three key hypoxic genes (HIF-1α, PAI-1, and VEGF-A) to normoxic states, indicating hypoxia reversal potential. Biosafety of the PLGA-ONBs was demonstrated in a rabbit model, demonstrating promise in clinical translation. The PLGA-ONBs developed exhibited excellent oxygen loading and retention, potential in hypoxia mitigation, and a safety profile that could be a promising route to treating ischemic diseases of the eye.

Polylactic Acid-Polyglycolic Acid Copolymer↗

PubMed2026

HIF1A+CSF3R+ neutrophils-dominated hypoxic niche induced metabolic reprogramming for neoadjuvant therapy resistance in NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the frequently occurring cancers characterized by molecular heterogeneity and multiple immune cell infiltration patterns, which are associated with treatment sensitivity and resistance. However, the specific microenvironmental cells and their mechanisms that lead to treatment resistance in patients need to be explored in greater depth. METHODS: On the basis of patients receiving neoadjuvant therapy in our center, a multicenter, multicohort NSCLC spatial transcriptome, single-cell transcriptome, T-cell receptor repertoire sequencing, bulk RNA transcriptome, phosphorylated proteome, genome mutation, and clinical data were included for a comprehensive assessment of the therapeutic and prognostic impact of HIF1A+ CSF3R+ neutrophils in NSCLC. In vitro experiments validated the functional phenotype of HIF1A+ CSF3R+ neutrophils and co-localization interactions with other cellular subpopulations. Gradient boosting machine (GBM) constructed region of interest (ROI) models for evaluation. Computer-aided drug design (CADD) was used to predict targeted small molecule drugs, and in vivo mouse models were constructed to assess the effectiveness of the combination treatment regimen. RESULTS: Centered on HIF1A+ CSF3R+ neutrophils, recruited exhausted T cells and stromal cells form a hypoxic niche within the tumor region, which was enriched in non-response patients. ROI composed of these specific cellular subpopulations, associated with senescence and glycolysis, accurately predicting NSCLC progression, prognosis, and microenvironment composition. CADD analysis identified that platycodin-D2 specifically targeted CSF3R, reducing HIF1A expression and inhibiting neutrophil activity. Combining navitoclax, platycodin-D2 with anti-programmed cell death protein 1 (PD-1) significantly suppressed tumor proliferation and improved the immunosuppressive microenvironment. CONCLUSION: Our study emphasized the role of HIF1A+ CSF3R+ neutrophils in immunotherapeutic resistance of NSCLC, constructed a microenvironmental immune dysregulation network in a hypoxic ecological niche with HIF1A+ CSF3R+ neutrophils as the center. Platycodin-D2 specifically targeted HIF1A+ CSF3R+ neutrophils, enhancing the efficacy of anti-PD-1 therapy in NSCLC.

Humans↗

PubMed2025

ALDOC and PGK1 coordinately induce glucose metabolism reprogramming and promote development of colorectal cancer.

Colorectal cancer (CRC) remains a significant health challenge globally, demanding a comprehensive understanding of its molecular underpinnings for effective management. In this study, we investigated the role of Aldolase C (ALDOC), a glycolytic enzyme, in CRC pathogenesis. Transcriptomic analysis of CRC tissues from The Cancer Genome Atlas (TCGA) revealed a substantial upregulation of ALDOC, correlating with adverse clinical outcomes. Immunohistochemical (IHC) staining of locally collected patient-derived tissues corroborated these findings, demonstrating elevated ALDOC expression in tumor tissues, particularly in advanced stages. Functional studies elucidated the regulatory role of ALDOC in CRC cell phenotypes. ALDOC knockdown significantly inhibited cell proliferation, induced apoptosis, arrested cell cycle progression, and suppressed cell migration in vitro. Moreover, in vivo studies using xenograft models confirmed that ALDOC knockdown attenuated tumor growth. Mechanistically, ALDOC was found to interact with hypoxia-inducible factor 1 alpha (HIF1A) and enhance its transcriptional activity on phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme. Dual-luciferase reporter assays and chromatin immunoprecipitation experiments validated the ALDOC-mediated transcriptional activation of PGK1. Further functional rescue experiments revealed a synergistic interplay between ALDOC and PGK1 in regulating CRC cell phenotypes. Additionally, ALDOC was implicated in promoting aerobic glycolysis in CRC cells, potentially through PGK1 regulation. Collectively, our findings unveil ALDOC as a critical regulator of CRC pathogenesis, offering insights into its potential as a therapeutic target and highlighting the ALDOC/PGK1 axis as a promising avenue for further investigation in CRC.

Humans↗

PubMed2024

Comprehensive analysis of circRNA-miRNA-mRNA network related to angiogenesis in recurrent implantation failure.

BACKGROUND: Abnormal endometrial blood flow causes a decrease in endometrial receptivity and is considered a relatively independent risk factor for recurrent implantation failure (RIF). This study aimed to explore the potentially functional circRNA-miRNA-mRNA network in RIF, and further explore its mechanism. METHODS: Datasets were downloaded from the GEO database to identify differentially expressed circRNAs, miRNAs and mRNAs. The circRNA-miRNA-mRNA and PPI networks were constructed using Cytoscape 3.6.0 and the STRING database, the hub genes were identified with the cytoHubba plug-in, and a circRNA-miRNA-hub mRNA regulatory sub-network was constructed. Then, GO and KEGG pathway enrichment analyses of the hub genes were performed to comprehensively analyze the mechanism of hub mRNAs in RIF. Due to the results of circRNAs-miRNAs-hub mRNAs regulatory network, we verified the expression of circRNA_0001721, circRNA_0000714, miR-17-5p, miR-29b-3p, HIF1A and VEGFA in the RIF mouse model by qRT‒PCR and western blotting. RESULTS: We initially identified 175 DEmRNAs, 48 DEmiRNAs and 56 DEcircRNAs in RIF associated with angiogenesis and constructed a circRNA-miRNA‒mRNA network and PPI network. We further identified six hub genes in the acquired network. Based on these genes, functional enrichment analysis revealed that the HIF-1 signaling pathway plays a vital role in endometrial angiogenesis in RIF. In addition, the interaction networks of circRNA_0001721/miR-17-5p/HIF1A and the circRNA_0000714/miR-29b-3p/VEGFA axis were predicted. In the RIF mouse model, circRNA_0001721, circRNA_0000714, HIF1A and VEGFA were down-regulated, whereas miR-17-5p and miR-29b-3p were up-regulated according to qRT‒PCR and western blotting. CONCLUSION: This study revealed that the HIF-1 signaling pathway plays a vital role in endometrial angiogenesis in RIF. The circRNA_0001721/miR-17-5p/HIF1A and circRNA_0000714/miR-29b-3p/VEGFA axes might play a role in the pathogenesis of endometrial angiogenesis in RIF.

MicroRNAs↗

PubMed2024

Bioinformatics analysis of ferroptosis in frozen shoulder.

OBJECTIVES: Frozen shoulder is a common shoulder disease that significantly affects the patient's life and work. Ferroptosis is a new type of programmed cell death, which is involved in many diseases. However, there have been no studies reporting the relationship between frozen shoulders and ferroptosis. This study identified potential molecular markers of ferroptosis in frozen shoulders to provide more effective strategies for the treatment of frozen shoulders. METHODS: GSE238053 was downloaded from the Gene Expression Omnibus (GEO) dataset and intersected with ferroptosis genes to obtain differentially expressed genes (DEGs). The signaling pathways and biological functions of DEGs were performed by WebGestalt and Metascape. The interactions related to these DEGs and the key genes between frozen shoulders and ferroptosis was performed by STRING and Cytoscape. A frozen shoulders rat model was used to validate our predicted genes, Western Blot and qRT-PCR was used to assess the expression levels of our genes of interest. RESULTS: A total of 34 DEGs between GSE238053 and Ferroptosis Database were obtained, most of which were involved in the HIF-1 signaling pathway and inflammatory response. A protein-protein interaction network was obtained by Cytoscape and the key genes (IL-6, HMOX1 and TLR4) were screened by MCODE. Our results of Western Blot showed that the protein expression level of TLR4 and HMOX1 were elevated, and the protein level of IL-6 decreased in frozen shoulders rat model. The mRNA level after frozen shoulders showed that IL-6 was upregulated, whereas TLR4 and HMOX1were downregulated. CONCLUSIONS: The results demonstrated that ferroptosis may affect the pathological process of frozen shoulders through these signaling pathways and genes. The identification of IL-6, HMOX1 and TLR4 genes can provide new therapeutic targets for frozen shoulders.

Ferroptosis↗

PubMed2026

The Triad of NF-κB, HIF-1α, and Oxidative Stress in Hepatocellular Carcinoma: Pathogenesis, Clinical Challenges, and Therapeutic Potential of CIGB-552 in Liver Transplantation.

Hepatocellular carcinoma (HCC) represents a formidable oncological challenge characterized by complex molecular pathogenesis and limited therapeutic outcomes, particularly in the context of liver transplantation. As the sixth most commonly diagnosed cancer and the third leading cause of cancer-related mortality worldwide, HCC poses significant clinical challenges that demand innovative therapeutic approaches. Central to HCC development and progression is a pathogenic triad comprising nuclear factor-kappa B (NF-κB), hypoxia-inducible factor-1α (HIF-1α), and oxidative stress-three interconnected pathways that drive inflammation, angiogenesis, metabolic reprogramming, and cell survival. This comprehensive review examines the molecular mechanisms underlying this triad in HCC pathogenesis across different etiological contexts, including viral hepatitis and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). We critically analyse the unique clinical challenges posed by HCC in liver transplantation recipients, particularly the paradoxical requirement for immunosuppression alongside antitumor immunity, and constraints surrounding immunotherapy application. Furthermore, we present CIGB-552, a novel peptide therapeutic targeting COMMD1 (Copper Metabolism MURR1 Domain-containing protein 1), as a promising dual-function agent capable of simultaneously disrupting the pathogenic triad through NF-κB inhibition, HIF-1α suppression, and strategic modulation of oxidative stress via SOD1 regulation. The multimodal mechanism of CIGB-552 offers a theoretically rational therapeutic approach for HCC management in both pre-transplant and post-transplant settings. Clinical validation in the transplantation setting is required.

Humans↗