ArticleJCI insight2023
Hypoxia enhances IPF mesenchymal progenitor cell fibrogenicity via the lactate/GPR81/HIF1α pathway.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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The trial behind it
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 72 citations in OpenAlex.
- Network meta-analysis of pharmacological treatments for idiopathic pulmonary fibrosis: evaluating effects on lung function.Frontiers in pharmacology · 2026Pooled it
- Aerobic exercise enhances α-tubulin lactylation and neurological recovery after ischemic stroke.Cell & bioscience · 2026Article
- Multi-Omics Analysis Reveals New Insights into Yak Lung Under High-Altitude Adaptation.Animals : an open access journal from MDPI · 2026Article
- Piezo1 mediates hypoxia-induced endometriosis fibrosis via the mtDNA -dependent cGAS-STING pathway.Journal of translational medicine · 2026Article
- Elevated lactate production exacerbates PM2.5-induced pulmonary fibrosis by stabilizing TGF-β1.Journal of advanced research · 2026Article
- From Byproduct to Regulator: The Expanding Role of Lactate and Lactylation in Cardiovascular Physiology and Disease.Biology · 2026Review
- Lactate Metabolism-Immune Regulation-Related Gene Signature in Lower-Grade Gliomas: Prognostic Model Development and Immune Characterization.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Optimized culture of primary human alveolar type II cell-derived 3D organoids from fibrotic lung tissue with phenotypic and metabolic profiling.Respiratory research · 2026Article
- Parathyroid hormone-related protein is a therapeutic target in idiopathic pulmonary fibrosis.Signal transduction and targeted therapy · 2026Article
- Beyond a metabolite: lactate and lactylation in lung diseases.Respiratory research · 2026Review
- Septic Shock Caused by Coinfection of Shewanella algae Bloodstream Infection and Epstein-Barr Virus: Clinical Characteristics and Genomic Analysis.MicrobiologyOpen · 2026Article
- Lactate: elucidating its indispensable role in human health.Molecular cancer · 2026Review
- Obesity-induced metabolic reprogramming of the tumor immune microenvironment: mechanisms, spatial niches, and immunotherapy response.Frontiers in immunology · 2026Review
- Type 2 Inflammatory Diseases: The Crossroads of Immunity and Metabolism.Research (Washington, D.C.) · 2026Review
- Epigenetic regulatory mechanisms and translational applications in idiopathic pulmonary fibrosis.American journal of clinical and experimental immunology · 2026Review
- Reprogrammed Fibrotic Niche Fuels Lung Cancer Initiation and Reciprocal Remodeling.International journal of biological sciences · 2026Review
- Mesenchymal stem cells and derived extracellular vesicles in major respiratory diseases: from multifaceted molecular mechanisms to clinical perspectives.Frontiers in cell and developmental biology · 2026Review
- Modulation of an aberrant basal cell program in human alveolar epithelial spheroids and lung slices.Respiratory research · 2025Article
- Role of metabolic reprogramming of cancer‑associated fibroblasts in tumor development and progression (Review).International journal of oncology · 2025Review
- Lactylation in Cardiovascular Diseases: Current Progress and Perspectives.Journal of the American Heart Association · 2025Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Hypoxia is a sentinel feature of idiopathic pulmonary fibrosis (IPF). The IPF microenvironment contains high lactate levels, and hypoxia enhances cellular lactate production. Lactate, acting through the GPR81 lactate receptor, serves as a signal molecule regulating cellular processes. We previously identified intrinsically fibrogenic mesenchymal progenitor cells (MPCs) that drive fibrosis in the lungs of patients with IPF. However, whether hypoxia enhances IPF MPC fibrogenicity is unclear. We hypothesized that hypoxia increases IPF MPC fibrogenicity via lactate and its cognate receptor GPR81. Here we show that hypoxia promotes IPF MPC self-renewal. The mechanism involves hypoxia-mediated enhancement of LDHA function and lactate production and release. Hypoxia also increases HIF1α levels, and this increase in turn augments the expression of GPR81. Exogenous lactate operating through GPR81 promotes IPF MPC self-renewal. IHC analysis of IPF lung tissue demonstrates IPF MPCs expressing GPR81 and hypoxic markers on the periphery of the fibroblastic focus. We show that hypoxia enhances IPF MPC fibrogenicity in vivo. We demonstrate that knockdown of GPR81 inhibits hypoxia-induced IPF MPC self-renewal in vitro and attenuates hypoxia-induced IPF MPC fibrogenicity in vivo. Our data demonstrate that hypoxia creates a feed-forward loop that augments IPF MPC fibrogenicity via the lactate/GPR81/HIF1α pathway.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.