{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T05:19:03Z","timestamp":1787980743301,"version":"build-2784847793"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"GuangDong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2021A1515110456"],"award-info":[{"award-number":["2021A1515110456"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Sepsis-induced acute lung injury (SI-ALI) leads to high mortality in critically ill patients, and no specific targeted treatments are available. Current studies mainly characterize intercellular crosstalk via protein\u2013ligand\u2013receptor frameworks, while metabolite-derived immune signal transmission is largely unclarified. Alveolar macrophages are located at the alveolar barrier and may act as central metabolic coordinators to trigger neutrophil-mediated lung inflammation, yet the complete metabolite signaling network has not been systematically mapped. Methods: We integrated single-cell and bulk transcriptomic datasets from CLP-induced septic mouse lungs. CellChat and MEBOCOST were jointly used to reconstruct protein\u2013metabolite dual communication networks. LASSO regression and random forest were combined to screen core metabolic hub genes, followed by single-cell expression mapping and in vivo histology &amp; qPCR validation. Results: We identified a pivotal alveolar macrophage\u2013neutrophil immunometabolic axis dominated by iron-Slc40a1 and LTB4-Ltb4r1 signaling. Three hub genes (Pmvk, Slc2a1, Slc7a11) coordinately regulate inflammatory pathways, among which myeloid-enriched Slc7a11 balances cellular redox and paracrine inflammatory responses. Conclusions: This study establishes the first dual-layer cell communication atlas for SI-ALI, proposes a macrophage-centered metabolic inflammatory regulatory model, and highlights Slc7a11 as a potential therapeutic target for septic lung injury.<\/jats:p>","DOI":"10.3390\/genes17091019","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:03:43Z","timestamp":1787832223000},"page":"1019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-Cell RNA Sequencing Combined with MEBOCOST Reveals Alveolar Macrophage-Mediated Immunometabolic Communication Mechanisms in Sepsis-Induced Acute Lung Injury"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0296-0502","authenticated-orcid":false,"given":"Lixia","family":"Zhao","sequence":"first","affiliation":[{"name":"Shenzhen School of Clinical Medicine, Southern Medical University, Shenzhen 518110, China"},{"name":"Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen 518110, China"},{"name":"Department of Anesthesiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuming","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2916-2073","authenticated-orcid":false,"given":"Youtan","family":"Liu","sequence":"additional","affiliation":[{"name":"Shenzhen School of Clinical Medicine, Southern Medical University, Shenzhen 518110, China"},{"name":"Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen 518110, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_2","unstructured":"GBD 2021 Sepsis Collaborators (2025). Global, regional, and national sepsis incidence and mortality, 1990\u20132021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet Glob. Health, 13, e2013\u2013e2026."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/S0140-6736(21)00439-6","article-title":"Acute respiratory distress syndrome","volume":"398","author":"Meyer","year":"2021","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1056\/NEJMra2403213","article-title":"Sepsis and septic shock","volume":"391","author":"Meyer","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sun, B., Lei, M., Zhang, J., Kang, H., Liu, H., and Zhou, F. (2023). Acute lung injury caused by sepsis: How does it happen?. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1289194"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kumar, V. (2020). Pulmonary innate immune response determines the outcome of inflammation during pneumonia and sepsis-associated acute lung injury. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01722"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nri.2016.70","article-title":"A guide to immunometabolism for immunologists","volume":"16","author":"Kishton","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Pan, R., Sun, Y., Chen, L., Pan, J., and Guo, J. (2026). Macrophage metabolic reprogramming in sepsis-associated acute lung injury: Mechanisms and therapeutic strategies. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1808474"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7884","DOI":"10.1074\/jbc.M113.522037","article-title":"Metabolic reprogramming of macrophages: Glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype","volume":"289","author":"Freemerman","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate is a danger signal that induces IL-1\u03b2 via HIF-1\u03b1","volume":"496","author":"Tannahill","year":"2013","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wang, L., Zhang, W., and Feng, X. (2025). Ferroptosis in sepsis induced acute lung injury\/acute respiratory distress syndrome (ALI\/ARDS): A potential therapeutic strategy. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1689155"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.jaci.2023.06.013","article-title":"Phosphomevalonate kinase deficiency expands the genetic spectrum of systemic autoinflammatory diseases","volume":"152","author":"Berner","year":"2023","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/ni.3487","article-title":"Control of the innate immune response by the mevalonate pathway","volume":"17","author":"Akula","year":"2016","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3205","DOI":"10.2147\/JIR.S419576","article-title":"Single-cell RNA sequencing and transcriptome analysis revealed the immune microenvironment and gene markers of acute respiratory distress syndrome","volume":"16","author":"He","year":"2023","journal-title":"J. Inflamm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1038\/s41556-021-00796-6","article-title":"A single-cell transcriptomic landscape of the lungs of patients with COVID-19","volume":"23","author":"Wang","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1038\/s41591-023-02327-2","article-title":"An integrated cell atlas of the lung in health and disease","volume":"29","author":"Sikkema","year":"2023","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"106025","DOI":"10.1016\/j.ebiom.2025.106025","article-title":"A unified single-cell atlas of human lung provides insights into pulmonary diseases","volume":"122","author":"Wu","year":"2025","journal-title":"eBioMedicine"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Wang, F., Chen, M., Ma, J., Wang, C., Wang, J., Xia, H., Zhang, D., and Yao, S. (2022). Integrating bulk and single-cell sequencing reveals the phenotype-associated cell subpopulations in sepsis-induced acute lung injury. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.981784"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3870","DOI":"10.1038\/s41467-023-39593-0","article-title":"Single cell transcriptomics identifies distinct profiles in pediatric acute respiratory distress syndrome","volume":"14","author":"Flerlage","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"gkaf569","DOI":"10.1093\/nar\/gkaf569","article-title":"MEBOCOST maps metabolite-mediated intercellular communications using single-cell RNA-seq","volume":"53","author":"Zheng","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100434","DOI":"10.1016\/j.patter.2022.100434","article-title":"scTenifoldKnk: An efficient virtual knockout tool for gene function predictions via single-cell gene regulatory network perturbation","volume":"3","author":"Osorio","year":"2022","journal-title":"Patterns"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1016\/j.immuni.2022.08.010","article-title":"Biology of lung macrophages in health and disease","volume":"55","author":"Aegerter","year":"2022","journal-title":"Immunity"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e170501","DOI":"10.1172\/JCI170501","article-title":"Alveolar macrophages in tissue homeostasis, inflammation, and infection: Evolving concepts of therapeutic targeting","volume":"133","author":"Malainou","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41577-023-00848-y","article-title":"Tissue-specific macrophages: How they develop and choreograph tissue biology","volume":"23","author":"Mass","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s12931-021-01722-y","article-title":"Nutritional immunity: The impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease","volume":"22","author":"Healy","year":"2021","journal-title":"Respir. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.bbrc.2016.06.003","article-title":"Contrasting intra- and extracellular distribution of catalytic ferrous iron in ovalbumin-induced peritonitis","volume":"476","author":"Ito","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1182\/bloodadvances.2020002198","article-title":"Neutrophils from hereditary hemochromatosis patients are protected from iron excess and are primed","volume":"4","author":"Renassia","year":"2020","journal-title":"Blood Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.devcel.2012.02.003","article-title":"LTB4 Is a Signal-Relay Molecule during Neutrophil Chemotaxis","volume":"22","author":"Afonso","year":"2012","journal-title":"Dev. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7866","DOI":"10.1073\/pnas.79.24.7866","article-title":"Human alveolar macrophages produce leukotriene B4","volume":"79","author":"Fels","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e201910215","DOI":"10.1083\/jcb.201910215","article-title":"The LTB4-BLT1 axis regulates actomyosin and \u03b22-integrin dynamics during neutrophil extravasation","volume":"219","author":"Subramanian","year":"2020","journal-title":"J. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.4049\/jimmunol.174.6.3617","article-title":"Involvement of BLT1 endocytosis and Yes kinase activation in leukotriene B4-induced neutrophil degranulation","volume":"174","author":"Gaudreault","year":"2005","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2350779","DOI":"10.1002\/eji.202350779","article-title":"Leukotriene B4-induced neutrophil extracellular traps impede the clearance of Pneumocystis","volume":"54","author":"Zhou","year":"2024","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nrm.2015.11","article-title":"Protein prenylation: Unique fats make their mark on biology","volume":"17","author":"Wang","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.cmet.2025.03.004","article-title":"Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation","volume":"37","year":"2025","journal-title":"Cell Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: Mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1038\/s42003-024-07072-x","article-title":"Decoding the multiple functions of ZBP1 in the mechanism of sepsis-induced acute lung injury","volume":"7","author":"Gong","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3578","DOI":"10.4049\/jimmunol.152.7.3578","article-title":"Involvement of the cystine transport system xc- in the macrophage-induced glutamate-dependent cytotoxicity to neurons","volume":"152","author":"Piani","year":"1994","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6695","DOI":"10.4049\/jimmunol.177.10.6695","article-title":"Glutamate released by dendritic cells as a novel modulator of T cell activation","volume":"177","author":"Pacheco","year":"2006","journal-title":"J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s00011-026-02222-9","article-title":"Myeloid-derived suppressor cells in sepsis: Drivers of persistent immunosuppression and targets for precision immunotherapy","volume":"75","author":"Wang","year":"2026","journal-title":"Inflamm. Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1019\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T04:51:03Z","timestamp":1787979063000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091019"],"URL":"https:\/\/doi.org\/10.3390\/genes17091019","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]}}}