ArticleNature metabolism2024
Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells.
Article in Nature metabolism, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Intensification versus combination: revisiting the past and envisioning the future of LDHA inhibitors.Cancer chemotherapy and pharmacology · 2026Review
- Impaired Lung BCAA Metabolism Promotes Ferroptosis and Resultant Pulmonary Arterial Hypertension-Associated Hepatopathy.JACC. Basic to translational science · 2026Article
- Protocol for metabolite extraction and sample preparation from primary astrocytes for mass spectrometry-based metabolomic analysis.STAR protocols · 2026Article
- Tumor-derived branched-chain α-keto acids activate Notch signaling in tumor-associated macrophages to limit immunity.Nature immunology · 2026Article
- Branched-chain α-keto acids impair glucose-stimulated insulin secretion in pancreatic β-cells under diabetes by reactivating the LDHA-lactate axis.Nature communications · 2026Article
- Glucose Metabolic Enzyme PFKFB3 in Cardiopulmonary Vascular Health and Disease.Circulation research · 2026Review
- Vascular Smooth Muscle Cell-Specific BCAT2 Deficiency Attenuates Diabetic Atherosclerotic Calcification via Histone Propionylation.Research (Washington, D.C.) · 2026Article
- Glycolytic reprogramming and immune responses in macrophages: a crosstalk driven by bacterial infection.Frontiers in immunology · 2026Review
- Hypoxic microenvironment and pulmonary hypertension.Respiratory research · 2025Review
- Exploring the impact of endocrine-disrupting chemicals on erectile dysfunction through network toxicology and machine learning.BMC pharmacology & toxicology · 2025Article
- Genome wide DNA methylation and transcriptome integration analysis reveals potential markers in type A aortic dissection pathogenesis.Scientific reports · 2025Article
- Novel role of L-2-HG in regulating HIF1A signaling pathway and iron death resistance in renal cancer brain metastasis.Cell death & disease · 2025Article
- Identifying potential drugs for treating Cardiovascular-kidney metabolic syndrome via reverse network pharmacology.Frontiers in pharmacology · 2025Article
- Targeting the SMURF2-HIF1α axis: a new frontier in cancer therapy.Frontiers in oncology · 2024Review
Corrections and comments
- Erratum issued
- Update of
Authors and funding
12 authors.
Funding
Abstract
Hypoxia-inducible factor 1α (HIF1α) is a master regulator of biological processes in hypoxia. Yet, the mechanisms and biological consequences of aerobic HIF1α activation by intrinsic factors, particularly in normal (primary) cells, remain elusive. Here we show that HIF1α signalling is activated in several human primary vascular cells in normoxia and in vascular smooth muscle cells of normal human lungs. Mechanistically, aerobic HIF1α activation is mediated by paracrine secretion of three branched-chain α-ketoacids (BCKAs), which suppress PHD2 activity via direct inhibition and via LDHA-mediated generation of L-2-hydroxyglutarate. BCKA-mediated HIF1α signalling activation stimulated glycolytic activity and governed a phenotypic switch of pulmonary artery smooth muscle cells, which correlated with BCKA metabolic dysregulation and pathophenotypic changes in pulmonary arterial hypertension patients and male rat models. We thus identify BCKAs as previously unrecognized signalling metabolites that aerobically activate HIF1α and that the BCKA-HIF1α pathway modulates vascular smooth muscle cell function, an effect that may be relevant to pulmonary vascular pathobiology.
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