Lactate-fueled enzyme rewrites gene expression to drive pulmonary arterial hypertension

Pulmonary arterial hypertension, a relentless and often fatal disease in which the blood vessels of the lungs progressively narrow and stiffen, has long resisted therapies that go beyond easing symptoms. Now a team of researchers working at Fujian Medical University has uncovered a striking mechanism that may explain why the diseased vessels keep remodeling themselves even when current vasodilator drugs are applied. In a study published in iScience, the investigators report that lactate, the metabolic molecule long dismissed as cellular exhaust, appears to act as an epigenetic signal in pulmonary arterial hypertension, chemically decorating histones in a way that switches on a key remodeling gene. The finding ties the disease’s famous metabolic quirk directly to gene regulation and points to a new therapeutic axis.

The core pathology of pulmonary arterial hypertension is concentric remodeling of the pulmonary vasculature, driven mainly by the abnormal behavior of pulmonary artery smooth muscle cells. These cells proliferate excessively, migrate aggressively, and refuse to undergo apoptosis, gradually thickening the vessel walls and raising pulmonary vascular resistance until the right side of the heart fails under the strain. Although vasodilator-based therapies can alleviate symptoms to some extent, they are ineffective in reversing established vascular remodeling, which is why the search for strategies targeting this fundamental pathological process has become so urgent.

Metabolic reprogramming has attracted considerable attention in this context. Much like the Warburg effect seen in tumors, pulmonary artery smooth muscle cells preferentially utilize glycolysis over oxidative phosphorylation to generate energy even under normoxic conditions. This metabolic shift fuels lactate accumulation and drives a proliferative, apoptosis-resistant phenotypic switch in the cells. The cellular lactate flux essential for this pathway is regulated by monocarboxylate transporters, and MCT4, also known as SLC16A3, in particular facilitates lactate export. Its elevated expression is linked to poor prognosis in cancers such as rectal carcinoma, indicating its role in sustaining a high-glycolytic and proliferative state, which made its contribution to the metabolic phenotype of pulmonary arterial hypertension a compelling question.

Beyond being a metabolic byproduct, lactate is now recognized as a signaling molecule and a substrate for histone lysine lactylation, an epigenetic modification that directly links metabolism to gene regulation. Histone H3 lysine 18 lactylation, or H3K18la, has been shown to be associated with the activation of genes involved in inflammation and proliferation. Yet whether and how this lactate-driven epigenetic mechanism contributes to the pathogenesis of pulmonary arterial hypertension remained largely unexplored, as did the identity of the enzymes responsible for generating the key donors of the lactylation modification in pulmonary artery smooth muscle cells. Recently, alanyl-tRNA synthetase 1, or AARS1, a classical enzyme involved in protein synthesis, has been reported to function as a lactyltransferase in certain pathological contexts, translocating to the nucleus upon lactate accumulation in gastric cancer and diabetes, but its participation in lactate-mediated epigenetic regulation in pulmonary arterial hypertension had not been tested.

To probe these questions, the researchers employed a monocrotaline-induced rat model of pulmonary arterial hypertension alongside platelet-derived growth factor-BB-stimulated pulmonary artery smooth muscle cells in vitro. The monocrotaline model successfully reproduced the disease, with markedly elevated right ventricular systolic pressure and characteristic echocardiographic and hemodynamic phenotypes, including increased pulmonary artery diameter and shortened pulmonary arterial acceleration time. When the animals were treated with oxamate, an inhibitor of lactate dehydrogenase, these abnormal parameters were reversed. Parameters reflecting right ventricular structure, including end-diastolic and end-systolic diameters and wall thickness, were significantly increased after monocrotaline injection but significantly reduced by oxamate treatment, while right ventricular function parameters such as tricuspid annular plane systolic excursion, fractional shortening, and fractional area change were similarly restored.

Histological analysis of lung tissues showed marked pulmonary arteriole remodeling in the diseased animals, evidenced by increased wall area and wall thickness percentages on hematoxylin and eosin staining, vascular fibrosis on Masson’s trichrome staining, and enhanced alpha-smooth muscle actin expression on immunohistochemistry. Oxamate treatment effectively attenuated this vascular remodeling and significantly reduced the right ventricular hypertrophy index. Consistent with the metabolic shift observed in the disease, lactate levels were significantly elevated in the plasma and lung tissues of the monocrotaline rats. This was accompanied by increased protein expression of the lactate transporter MCT4, elevated global protein lactylation, and increased H3K18la levels, and oxamate treatment reduced lactate levels while concomitantly decreasing the levels of these lactylation-related markers.

The elevated H3K18la levels in the diseased lungs were associated with significant upregulation of proliferating cell nuclear antigen, a proliferation marker, and vimentin, a migration marker, and these changes were effectively reversed by oxamate intervention, linking lactate metabolism to disease-driving cellular phenotypes. Immunohistochemical staining further showed a significant increase in the proliferation marker Ki-67 in the pulmonary arteries, which oxamate markedly reduced. At the cellular level, primary rat pulmonary artery smooth muscle cells stimulated with platelet-derived growth factor-BB increased the expression of MCT4, H3K18la, PCNA, and vimentin, and co-treatment with oxamate reversed these effects while attenuating the growth factor-driven increase in cell viability. Exogenous lactate at 20 millimolar increased H3K18la levels, promoted proliferation as shown by EdU assay, and enhanced migration in both scratch wound-healing and Transwell assays, with oxamate abolishing each of these lactate-driven responses.

Gain- and loss-of-function experiments then clarified MCT4’s role in regulating lactylation. Overexpression of MCT4 by plasmid transfection elevated H3K18la levels in the cells, while small interfering RNA-mediated knockdown of MCT4 significantly reduced both MCT4 and H3K18la levels compared with negative control siRNA. The team then turned to AARS1 as a putative regulator of the modification. AARS1 was upregulated in the lungs of the monocrotaline group and in growth factor-stimulated cells, and this upregulation was attenuated by oxamate treatment, suggesting that AARS1 may be responsive to lactate availability. Molecular docking and structural analysis predicted a potential interaction between lactate and the catalytic pocket of AARS1, involving residues PHE98, HIS95, HIS94, and ARG246. When AARS1 was knocked down in cells treated with exogenous lactate, the increases in H3K18la and PCNA levels were attenuated, and immunofluorescence analysis showed increased nuclear localization of AARS1 following lactate treatment, providing a plausible spatial basis for its association with histone regulation.

The study also identified a possible counterweight to this modification. HDAC1 expression was significantly reduced in the lungs of the monocrotaline group, and lactate treatment decreased HDAC1 expression in the cells in vitro. Treatment with ITSA-1, a pharmacological activator of HDAC activity, attenuated the lactate-induced increase in H3K18la levels, supporting a potential role for HDAC1 in histone delactylation and suggesting that reduced HDAC1 expression in pulmonary arterial hypertension may contribute to the accumulation of the lactylation mark. The downstream effector emerged as beta-catenin, the core mediator of Wnt signaling and a well-established driver of smooth muscle cell proliferation and vascular remodeling. Beta-catenin protein levels were increased in the diseased rats and stimulated cells in a manner associated with lactate and lactylation, and exogenous lactate increased Ctnnb1 mRNA levels. Crucially, chromatin immunoprecipitation followed by quantitative PCR demonstrated enrichment of H3K18la at the promoter region of the Ctnnb1 gene, an enrichment enhanced by lactate and attenuated by oxamate, suggesting that lactate-derived histone lactylation may contribute directly to transcriptional upregulation of the remodeling-associated gene.

The authors are careful to frame their conclusions as a proposed pathway rather than a closed case. They acknowledge that the potential contributions of other lactylation-related enzymes, such as CBP and p300, and candidate delactylases, such as SIRT1 to SIRT3, remain unclear and warrant further investigation. Complementary gain-of-function and rescue experiments, including AARS1 overexpression, active-site mutagenesis, and in vivo validation, are required to establish causality. The study lacks direct validation in human pulmonary arterial tissues and patient-derived cells, species-specific differences may limit extrapolation, and the exclusive use of male animals limits generalizability to females. Direct transcriptional regulation of Ctnnb1 by H3K18la would also benefit from promoter reporter assays. Even so, the work expands the current understanding of lactate from a metabolic byproduct to a potential epigenetic regulator and suggests that the AARS1-H3K18la axis may represent a promising therapeutic target warranting further exploration for pulmonary arterial hypertension, a disease in desperate need of strategies that reverse remodeling rather than merely dilate vessels.

Subject of Research: Lactate-driven histone lactylation by AARS1 promotes pulmonary arterial hypertension

Article Title: Lactate-driven histone lactylation by AARS1 promotes pulmonary arterial hypertension

Article References: Chen, Z., Cai, Z., Lin, Y., Chen, A., Cao, R., Yu, L., Cai, K., Lian, G., & Xie, L. (2026). Lactate-driven histone lactylation by AARS1 promotes pulmonary arterial hypertension. iScience, 29(11), Article 117911. https://doi.org/10.1016/j.isci.2026.117911

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117911

Keywords: Lactate-driven, histone, lactylation, AARS1, promotes, pulmonary, arterial, hypertension, scientific research