ArticleCell communication and signaling : CCS2025
Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition.
Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The lactate-lactylation axis in renal fibrosis: potential mechanisms in diabetic kidney disease.Annals of medicine · 2025Pooled it
- Cancer-derived lactic acid as a potential upstream contributor to tumor hypoxia.Communications biology · 2026Review
- Lactate metabolism and protein lactylation in programmed cell death: From novel mechanism to therapeutic strategies in human diseases.Clinical and translational medicine · 2026Review
- Post-translational modifications in Neuroimmune cells during neuroinflammation: integrated regulatory networks and therapeutic opportunities.Biology direct · 2026Review
- Lactylation Remodels Tumorigenesis, Immune Microenvironment, and Therapeutic Response.Current issues in molecular biology · 2026Review
- Blastocyst-Derived Lactic Acid Regulates Uterine Epithelial Receptivity and Stromal Decidualization via the HIF1α-HO-1-Heme Metabolic Axis.Antioxidants (Basel, Switzerland) · 2026Article
- Hypoxia-inducible factor-1: A new neuroprotective agent for the treatment of hyperglycemia after stroke.Neural regeneration research · 2026Article
- P53 Competitively Binds P300 to Suppress HIF-1α/TFRC-Mediated Ferroptosis and Promote Doxorubicin Resistance in Breast Cancer.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Lactate metabolism and protein lactylation in inflammatory and tumor microenvironments.Molecular biomedicine · 2026Review
- The crosstalk between RNA m6A modification and protein lactylation: emerging insights into tumor progression.Oncogene · 2026Review
- Glucose Transporter 1 in Health and Disease.MedComm · 2026Review
- Substrate stiffness regulates HIF-1α signalling via β1-integrin/myosin-2/NF-κB axis.Journal of translational medicine · 2026Article
- Wireless knee joint monitoring using biodegradable single-ended pressure sensor in osteoarthritis management.Science advances · 2026Article
- PHGDH loss promotes hypoxia tolerance through glycolytic reprogramming and enhanced HIF-1 activity.Cell death discovery · 2026Article
- Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Glycolytic lactylation modulates cell death decisions in diabetic kidney disease: Metabolic‑epigenetic interplay between ferroptosis and autophagy in fibrotic remodeling (Review).International journal of molecular medicine · 2026Review
- Unveiling lactylation: A novel frontier in the pathogenesis of diabetic nephropathy (Review).International journal of molecular medicine · 2026Review
- Lysine lactylation-mediated post-translational modification: Molecular mechanisms and therapeutic target exploration in tumour drug resistance.Clinical and translational medicine · 2026Review
- Lactate-Induced ZMYM2 K529 Lactylation Stabilizes ZMYM2 and Promotes Platinum Resistance in Ovarian Cancer.International journal of molecular sciences · 2026Article
- IL-36γ enhanced bactericidal effects of macrophages to Mycobacterium tuberculosis via the IFN-γ/HIF-1ɑ/glycolysis pathway.Respiratory research · 2026Article
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Authors and funding
9 authors.
Funding
Abstract
Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of cellular adaptation to hypoxia. Although prolyl hydroxylation-mediated degradation via the von Hippel-Lindau (VHL) ubiquitination complex is a well-established regulatory mechanism, the role of lactate-induced posttranslational modifications in HIF-1α stabilization remains incompletely understood. Here, we demonstrate that lactate induces lysine lactylation of HIF-1α at distinct residues across species-specifically, K644 in mice and K12 in humans and pigs-to increase protein stability by impairing VHL recognition. Mass spectrometry and mutagenesis analyses revealed that lactylation at these sites reduces K48-linked ubiquitination and proteasomal degradation, even when HIF-1α is hydroxylated. Structural modeling and functional assays revealed that lactylation sterically hinders VHL binding without affecting hydroxylation. Notably, lactylated HIF-1α exhibited increased transcriptional activity, as evidenced by increased promoter occupancy and upregulation of hypoxia-responsive genes (Vegfa, Glut1). Cross-species comparisons highlighted evolutionary divergence in lactylation sites while preserving the functional conservation of this modification. Our findings reveal that lactylation is a universal regulatory mechanism that overrides classical hydroxylation-dependent degradation, expanding our understanding of metabolic control over hypoxic signaling.
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