ArticleResearch (Washington, D.C.)2025
Progressive Deactivation of Hydroxylases Controls Hypoxia-Inducible Factor-1α-Coordinated Cellular Adaptation to Graded Hypoxia.
Article in Research (Washington, D.C.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Mechanisms Underlying the Coordination of EMT and Glycolysis Mediated by Hypoxia and Glucose.Current issues in molecular biology · 2026Article
- Integrated mechanisms and clinical relevance of exercise driven remodeling of the tumor immune microenvironment.Translational oncology · 2026Review
- A Mechanistic Model of the HIF-1/HIF-2 Switch Regulating Hypoxia-Induced Cancer Stemness.International journal of molecular sciences · 2026Article
- Microneedle-mediated delivery of Coptis chinensis-derived nanovesicles orchestrating antibacterial and macrophage reprogramming for comprehensive wound healing.Journal of nanobiotechnology · 2026Article
- From metabolic antagonism to homeostatic restoration: rewiring hepatic stellate cell bioenergetics for liver fibrosis reversal.Frontiers in medicine · 2026Review
- Roles of Cellular Neighborhoods in Lung Cancer.Journal of Cancer · 2026Review
- Oxidative stress as a nexus: Integrating mitophagy and ferroptosis in endometrial carcinogenesis (Review).Oncology letters · 2026Review
- Trabecular-Like Scaffold Dictates Osteogenesis via Fluid Shear Stress-Induced Metabolic Reprogramming through the CAV1-HIF-1α Axis.Research (Washington, D.C.) · 2026Article
- Advances in Clinical Trials of Boron Neutron Capture Therapy.Research (Washington, D.C.) · 2026Review
- Hypoxic Reprogramming of ACOX1-Driven HSP90AB1 Crotonylation Stabilizes Thioredoxin to Orchestrate Redox Homeostasis in Oral Squamous Cell Carcinoma.Research (Washington, D.C.) · 2026Article
- Hypoxia-Induced TGFBI Promotes Bladder Cancer Progression by Creating a Stemness Regulation Loop through Stabilizing the Disulfide Bonds of GDF15.Research (Washington, D.C.) · 2026Article
- Oxygenation: Nanotechnological Strategies for Conquering Tumor Hypoxia in Photodynamic Therapy.International journal of nanomedicine · 2026Review
- HIF-mediated hierarchical hypoxic adaptation, a novel paradigm in heart failure pathogenesis: is there a role for targeted therapies?Frontiers in pharmacology · 2026Review
- Hypoxia-induced histone lactylation promotes pulmonary arterial smooth muscle cells proliferation in pulmonary hypertension.Molecular and cellular biochemistry · 2025Article
- Contribution and Regulation of HIF-1α in Testicular Injury Induced by Diabetes Mellitus.Biomolecules · 2025Review
- UBE2V1 Promotes Hepatocellular Carcinoma Progression by Forming a Positive Feedback Loop with HIF-1α.Research (Washington, D.C.) · 2025Article
- Article
- Differential Effect of Acute and Chronic Exercise on Cardiac Angiogenesis Regulator: The Role of mRNA HIF-1Cardiology research and practice · 2025Article
Corrections and comments
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Graded hypoxia is a common microenvironment in malignant solid tumors. As a central regulator in the hypoxic response, hypoxia-inducible factor-1 (HIF-1) can induce multiple cellular processes including glycolysis, angiogenesis, and necroptosis. How cells exploit the HIF-1 pathway to coordinate different processes to survive hypoxia remains unclear. We developed an integrated model of the HIF-1α network to elucidate the mechanism of cellular adaptation to hypoxia. By numerical simulations and bifurcation analysis, we found that HIF-1α is progressively activated with worsening hypoxia due to the sequential deactivation of the hydroxylases prolyl hydroxylase domain enzymes and factor inhibiting HIF (FIH). Bistable switches control the activation and deactivation processes. As a result, glycolysis, immunosuppression, angiogenesis, and necroptosis are orderly elicited in aggravating hypoxia. To avoid the excessive accumulation of lactic acid during glycolysis, HIF-1α induces monocarboxylate transporter and carbonic anhydrase 9 sequentially to export intracellular hydrogen ions, facilitating tumor cell survival. HIF-1α-induced miR-182 facilitates vascular endothelial growth factor production to promote angiogenesis under moderate hypoxia. The imbalance between accumulation and removal of lactic acid in severe hypoxia may result in acidosis and induce cell necroptosis. In addition, the deactivation of FIH results in the destabilization of HIF-1α in anoxia. Collectively, HIF-1α orchestrates the adaptation of tumor cells to hypoxia by selectively inducing its targets according to the severity of hypoxia. Our work may provide clues for tumor therapy by targeting the HIF-1 pathway.
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