Lactate-driven histone lactylation by AARS1 promotes pulmonary arterial hypertension
Abstract
Glycolytic reprogramming drives lactate accumulation in pulmonary arterial hypertension (PAH). We used a monocrotaline-induced rat PAH model and platelet-derived growth factor-BB (PDGF-BB)-stimulated pulmonary artery smooth muscle cells (PASMCs), together with oxamate intervention and molecular assays, to investigate lactate-mediated histone lactylation. PAH tissues exhibited increased lactate, MCT4, and histone H3 lysine 18 lactylation (H3K18la), accompanied by reduced HDAC1. Oxamate reversed these alterations and alleviated pulmonary vascular remodeling. Manipulating MCT4 expression modulated H3K18la levels. Upregulated alanyl-tRNA synthetase 1 (AARS1) displayed enhanced nuclear localization after lactate exposure; AARS1 depletion suppressed lactate-triggered H3K18la and PASMC proliferation. H3K18la was enriched at the Ctnnb1 promoter and correlated with enhanced Ctnnb1 transcription. These findings suggest that lactate may act as an epigenetic signal, linking glycolysis to Ctnnb1 activation through AARS1-associated H3K18la, thereby offering a potential target for PAH treatment.
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BibTeX
@article{chen2026lactatedriven,
title = {{Lactate-driven histone lactylation by AARS1 promotes pulmonary arterial hypertension}},
author = {Zhihai Chen and Zhidian Cai and Yifei Lin and Ai Chen and Rong Cao and Lingfeng Yu and Kexing Cai and Guili Lian and Liangdi Xie},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117911},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03294-3},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Lactate-driven histone lactylation by AARS1 promotes pulmonary arterial hypertension
AU - Zhihai Chen
AU - Zhidian Cai
AU - Yifei Lin
AU - Ai Chen
AU - Rong Cao
AU - Lingfeng Yu
AU - Kexing Cai
AU - Guili Lian
AU - Liangdi Xie
PY - 2026
DA - 2026/10/19
JO - iScience
DO - 10.1016/j.isci.2026.117911
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03294-3
AB - Glycolytic reprogramming drives lactate accumulation in pulmonary arterial hypertension (PAH). We used a monocrotaline-induced rat PAH model and platelet-derived growth factor-BB (PDGF-BB)-stimulated pulmonary artery smooth muscle cells (PASMCs), together with oxamate intervention and molecular assays, to investigate lactate-mediated histone lactylation. PAH tissues exhibited increased lactate, MCT4, and histone H3 lysine 18 lactylation (H3K18la), accompanied by reduced HDAC1. Oxamate reversed these alterations and alleviated pulmonary vascular remodeling. Manipulating MCT4 expression modulated H3K18la levels. Upregulated alanyl-tRNA synthetase 1 (AARS1) displayed enhanced nuclear localization after lactate exposure; AARS1 depletion suppressed lactate-triggered H3K18la and PASMC proliferation. H3K18la was enriched at the Ctnnb1 promoter and correlated with enhanced Ctnnb1 transcription. These findings suggest that lactate may act as an epigenetic signal, linking glycolysis to Ctnnb1 activation through AARS1-associated H3K18la, thereby offering a potential target for PAH treatment.
SN - 2589-0042
ER -