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

LDHA-Dependent Aerobic Glycolysis Shapes Pro-fibrotic Myeloid Cell Fate through Histone Lactylation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article LDHA-Dependent Aerobic Glycolysis Shapes Pro-fibrotic Myeloid Cell Fate through Histone Lactylation Feilong Wang, Wenjuan He, Chunmei Feng, Dongmei Liu, Song Zhang, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8834018/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version 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. Biological sciences/Immunology/Innate immunity Health sciences/Diseases/Immunological disorders/Inflammatory diseases Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTableS1.docx Supplementary Table S1 SupplementaryTableS2.docx Supplementary Table S2 SupplementaryFigures.pptx Supplementary Figures SupplementaryFiguresInfo.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8834018","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":595863929,"identity":"0dcb3250-923f-4017-bc0b-ce01b4a8ba8b","order_by":0,"name":"Feilong 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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. 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