LDHA-Dependent Aerobic Glycolysis Shapes Pro-fibrotic Myeloid Cell Fate through Histone Lactylation

Abstract

Abstract Metabolic reprogramming is a fundamental determinant of immune cell fate and effector function during inflammation, yet how distinct metabolic pathways regulate pathogenic lung macrophage activity and contribute to fibrotic remodeling remains incompletely understood. Here, we integrated single-cell RNA sequencing, lineage-specific genetic mouse models, and fate-mapping approaches to define the metabolic pathways that regulate the pro-fibrotic activity of lung macrophages. We found that such cells undergo pronounced aerobic glycolysis in the bleomycin-induced mouse model of pulmonary fibrosis. Myeloid cell-specific depletion of lactate dehydrogenase A (Ldha), but not of mitochondrial pyruvate carrier (Mpc), markedly attenuated lung fibrosis and improved survival. Mechanistically, enhanced glycolytic flux increased lactate production, which promoted histone lysine lactylation and facilitated Arginase 1 (Arg1) expression in lung macrophages, thereby driving fibrotic progression. Using monocyte fate-mapping, we further demonstrated that Arg1 expression is largely restricted to recruited monocyte-derived macrophages rather than lung-resident macrophages. Notably, selective deletion of Ldha in granulocyte-monocyte progenitors and their progeny was sufficient to suppress Arg1 expression and reduce fibrosis severity. In human lung samples, we observed significantly elevated expression of ARG1 and key glycolytic enzymes in patients with idiopathic pulmonary fibrosis, despite species-specific differences in the immune cell types expressing ARG1. Together, these findings identify an aerobic glycolysis–lactate–histone lactylation axis that regulates pro-fibrotic myeloid cell function and represents a potential therapeutic target in pulmonary fibrosis.

Key findings

• ▸Lung macrophages undergo pronounced aerobic glycolysis in the bleomycin-induced mouse model of pulmonary fibrosis.
• ▸Myeloid cell-specific depletion of lactate dehydrogenase A (LDHA) markedly attenuated lung fibrosis and improved survival, whereas depletion of the mitochondrial pyruvate carrier did not.
• ▸Enhanced glycolytic flux increases lactate production, promoting histone lysine lactylation to facilitate Arginase 1 expression in lung macrophages.

Keywords

Identifiers

DOI

10.21203/rs.3.rs-8834018/v1

Journal

Research Square

Year

2026