{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T15:29:49Z","timestamp":1793633389782,"version":"4.5.1"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T00:00:00Z","timestamp":1793577600000},"content-version":"vor","delay-in-days":112,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"name":"Postgraduate Research & Practice Innovation Program of Jiangsu Province","award":["No.SJCX24-0947"],"award-info":[{"award-number":["No.SJCX24-0947"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["NO.82474318"],"award-info":[{"award-number":["NO.82474318"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Gao-Feng Academic Talent Training Project of Jiangsu Provincial Hospital of Chinese Medicine","award":["No.k2026yrc09"],"award-info":[{"award-number":["No.k2026yrc09"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Genome Med"],"DOI":"10.1186\/s13073-026-01716-9","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T11:34:25Z","timestamp":1783942465000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics and spatial proteomic profiling reveal novel AGXT2\u2212 PYCR3\u2212 macrophages and their phenotypes in metabolic dysfunction-associated steatotic liver disease"],"prefix":"10.1186","volume":"18","author":[{"given":"Tiansu","family":"Lv","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongshan","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ee","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutian","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixian","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxuan","family":"Huai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianhua","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuyuan","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangyi","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiqiao","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"key":"1716_CR1","doi-asserted-by":"publisher","first-page":"155248","DOI":"10.1016\/j.metabol.2022.155248","volume":"136","author":"L Valenzuela-Vallejo","year":"2022","unstructured":"Valenzuela-Vallejo L, Guatibonza-Garc\u00eda V, Mantzoros CS. Recent guidelines for non-alcoholic fatty liver disease (NAFLD)\/ fatty liver disease (FLD): are they already outdated and in need of supplementation? Metab Clin Exp. 2022;136:155248.","journal-title":"Metab Clin Exp"},{"key":"1716_CR2","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.jhep.2023.11.004","volume":"80","author":"ZM Younossi","year":"2024","unstructured":"Younossi ZM, Alqahtani SA, Alswat K, Yilmaz Y, Keklikkiran C, Funuyet-Salas J, et al. Global survey of stigma among physicians and patients with nonalcoholic fatty liver disease. J Hepatol. 2024;80:419\u201330.","journal-title":"J Hepatol"},{"key":"1716_CR3","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","volume":"79","author":"ME Rinella","year":"2023","unstructured":"Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79:1542\u201356.","journal-title":"J Hepatol"},{"key":"1716_CR4","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1016\/j.jhep.2023.08.030","volume":"79","author":"AL Hutchison","year":"2023","unstructured":"Hutchison AL, Tavaglione F, Romeo S, Charlton M. Endocrine aspects of metabolic dysfunction-associated steatotic liver disease (MASLD): beyond insulin resistance. J Hepatol. 2023;79:1524\u201341.","journal-title":"J Hepatol"},{"key":"1716_CR5","doi-asserted-by":"publisher","DOI":"10.1097\/hep.0000000000000735","author":"S Driessen","year":"2023","unstructured":"Driessen S, Francque SM, Anker SD, Castro Cabezas M, Grobbee DE, Tushuizen ME, et al. Metabolic dysfunction-associated steatotic liver disease and the heart. Hepatology. 2023. https:\/\/doi.org\/10.1097\/hep.0000000000000735.","journal-title":"Hepatology"},{"key":"1716_CR6","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.tem.2024.02.007","volume":"35","author":"L Miao","year":"2024","unstructured":"Miao L, Targher G, Byrne CD, Cao Y-Y, Zheng M-H. Current status and future trends of the global burden of MASLD. Trends Endocrinol Metab TEM. 2024;35:697\u2013707.","journal-title":"Trends Endocrinol Metab TEM"},{"key":"1716_CR7","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2024.02.007","author":"L Miao","year":"2024","unstructured":"Miao L, Targher G, Byrne CD, Cao Y-Y, Zheng M-H. Current status and future trends of the global burden of MASLD. Trends Endocrinol Metab. 2024. https:\/\/doi.org\/10.1016\/j.tem.2024.02.007.","journal-title":"Trends Endocrinol Metab"},{"key":"1716_CR8","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","volume":"15","author":"Z Younossi","year":"2018","unstructured":"Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11\u201320.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"1716_CR9","doi-asserted-by":"publisher","DOI":"10.1097\/hep.0000000000000860","author":"M Noureddin","year":"2024","unstructured":"Noureddin M. MASH clinical trials and drugs pipeline: an impending tsunami. Hepatology. 2024. https:\/\/doi.org\/10.1097\/hep.0000000000000860.","journal-title":"Hepatology"},{"key":"1716_CR10","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","volume":"24","author":"SL Friedman","year":"2018","unstructured":"Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24:908\u201322.","journal-title":"Nat Med"},{"key":"1716_CR11","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1001\/jama.2020.2298","volume":"323","author":"AC Sheka","year":"2020","unstructured":"Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic steatohepatitis: a review. JAMA. 2020;323:1175\u201383.","journal-title":"JAMA"},{"key":"1716_CR12","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1056\/NEJMoa2309000","volume":"390","author":"SA Harrison","year":"2024","unstructured":"Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497\u2013509.","journal-title":"N Engl J Med"},{"key":"1716_CR13","doi-asserted-by":"crossref","unstructured":"Bansal MB, Patton H, Morgan TR, Carr RM, Dranoff JA, Allen AM. Semaglutide therapy for metabolic dysfunction-associated steatohepatitis: November 2025 updates to AASLD Practice Guidance. Hepatology (Baltimore, Md.) 2025;83:1326\u20131340.","DOI":"10.1097\/HEP.0000000000001608"},{"key":"1716_CR14","doi-asserted-by":"crossref","unstructured":"Aizarani N, Saviano A, Sagar, Mailly L, Durand S, Herman JS, Pessaux P, et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 2019;572:199\u2013204.","DOI":"10.1038\/s41586-019-1373-2"},{"key":"1716_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.11.007","author":"RJ Arg\u00fcello","year":"2020","unstructured":"Arg\u00fcello RJ, Combes AJ, Char R, Gigan J-P, Baaziz AI, Bousiquot E, et al. SCENITH: a flow cytometry-based method to functionally profile energy metabolism with single-cell resolution. Cell Metab. 2020. https:\/\/doi.org\/10.1016\/j.cmet.2020.11.007.","journal-title":"Cell Metab"},{"key":"1716_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.07.028","author":"X Xiong","year":"2019","unstructured":"Xiong X, Kuang H, Ansari S, Liu T, Gong J, Wang S, et al. Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol Cell. 2019. https:\/\/doi.org\/10.1016\/j.molcel.2019.07.028.","journal-title":"Mol Cell"},{"key":"1716_CR17","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1016\/j.jhep.2022.06.004","volume":"77","author":"T Hendrikx","year":"2022","unstructured":"Hendrikx T, Porsch F, Kiss MG, Rajcic D, Papac-Mili\u010devi\u0107 N, Hoebinger C, et al. Soluble TREM2 levels reflect the recruitment and expansion of TREM2+ macrophages that localize to fibrotic areas and limit NASH. J Hepatol. 2022;77:1373\u201385.","journal-title":"J Hepatol"},{"key":"1716_CR18","doi-asserted-by":"publisher","unstructured":"Guilliams M, Bonnardel J, Haest B, Vanderborght B, Wagner C, Remmerie A, Bujko A, et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell. 2022. https:\/\/doi.org\/10.1016\/j.cell.2021.12.018.","DOI":"10.1016\/j.cell.2021.12.018"},{"key":"1716_CR19","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/s41575-018-0082-x","volume":"16","author":"K Kazankov","year":"2019","unstructured":"Kazankov K, J\u00f8rgensen SMD, Thomsen KL, M\u00f8ller HJ, Vilstrup H, George J, et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol. 2019;16:145\u201359.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"1716_CR20","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1002\/path.5275","volume":"248","author":"J Han","year":"2019","unstructured":"Han J, Zhang X, Lau JKC, Fu K, Lau HC, Xu W, et al. Bone marrow-derived macrophage contributes to fibrosing steatohepatitis through activating hepatic stellate cells. J Pathol. 2019;248:488\u2013500.","journal-title":"J Pathol"},{"key":"1716_CR21","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1053\/j.gastro.2019.11.311","volume":"158","author":"RF Schwabe","year":"2020","unstructured":"Schwabe RF, Tabas I, Pajvani UB. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology. 2020;158:1913\u201328.","journal-title":"Gastroenterology"},{"key":"1716_CR22","doi-asserted-by":"publisher","first-page":"115350","DOI":"10.1016\/j.celrep.2025.115350","volume":"44","author":"J Li","year":"2025","unstructured":"Li J, Chen X, Song S, Jiang W, Geng T, Wang T, et al. Hexokinase 2-mediated metabolic stress and inflammation burden of liver macrophages via histone lactylation in MASLD. Cell Rep. 2025;44:115350.","journal-title":"Cell Rep"},{"key":"1716_CR23","doi-asserted-by":"publisher","first-page":"eado3141","DOI":"10.1126\/sciadv.ado3141","volume":"10","author":"S Hu","year":"2024","unstructured":"Hu S, Li R, Gong D, Hu P, Xu J, Ai Y, et al. Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis. Sci Adv. 2024;10:eado3141.","journal-title":"Sci Adv"},{"key":"1716_CR24","doi-asserted-by":"publisher","first-page":"762564","DOI":"10.3389\/fimmu.2021.762564","volume":"12","author":"Z Gan","year":"2021","unstructured":"Gan Z, Zhang M, Xie D, Wu X, Hong C, Fu J, et al. Glycinergic signaling in macrophages and its application in macrophage-associated diseases. Front Immunol. 2021;12:762564.","journal-title":"Front Immunol"},{"key":"1716_CR25","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1038\/s41467-019-13858-z","volume":"11","author":"PD Piehowski","year":"2000","unstructured":"Piehowski PD, Zhu Y, Bramer LM, Stratton KG, Zhao R, Orton DJ, et al. Automated mass spectrometry imaging of over 2000 proteins from tissue sections at 100-\u03bcm spatial resolution. Nat Commun. 2000;11:8.","journal-title":"Nat Commun"},{"key":"1716_CR26","doi-asserted-by":"crossref","unstructured":"EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81:492\u2013542.","DOI":"10.1016\/j.jhep.2024.04.031"},{"key":"1716_CR27","doi-asserted-by":"publisher","first-page":"e1005112","DOI":"10.1371\/journal.pcbi.1005112","volume":"12","author":"H Chen","year":"2016","unstructured":"Chen H, Lau MC, Wong MT, Newell EW, Poidinger M, Chen J. Cytofkit: a Bioconductor package for an integrated mass cytometry data analysis pipeline. PLoS Comput Biol. 2016;12:e1005112.","journal-title":"PLoS Comput Biol"},{"key":"1716_CR28","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1126\/science.1198704","volume":"332","author":"SC Bendall","year":"2011","unstructured":"Bendall SC, Simonds EF, Qiu P, Amir E-aD, Krutzik PO, Finck R, et al. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science (New York, NY). 2011;332:687\u201396.","journal-title":"Science (New York, NY)"},{"key":"1716_CR29","doi-asserted-by":"publisher","first-page":"e43","DOI":"10.1002\/imt2.43","volume":"1","author":"Z Gu","year":"2022","unstructured":"Gu Z. Complex heatmap visualization. IMeta. 2022;1:e43.","journal-title":"IMeta"},{"key":"1716_CR30","first-page":"5535","volume":"36","author":"DG Bunis","year":"2021","unstructured":"Bunis DG, Andrews J, Fragiadakis GK, Burt TD, Sirota M. dittoSeq: universal user-friendly single-cell and bulk RNA sequencing visualization toolkit. Bioinformatics (Oxford, England). 2021;36:5535\u20136.","journal-title":"Bioinformatics (Oxford, England)"},{"key":"1716_CR31","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1021\/acs.jproteome.7b00602","volume":"17","author":"CD Kelstrup","year":"2017","unstructured":"Kelstrup CD, Bekker-Jensen DB, Arrey TN, Hogrebe A, Harder A, Olsen JV. Performance evaluation of the Q Exactive HF-X for shotgun proteomics. J Proteome Res. 2017;17:727\u201338.","journal-title":"J Proteome Res"},{"key":"1716_CR32","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1038\/nprot.2016.136","volume":"11","author":"S Tyanova","year":"2016","unstructured":"Tyanova S, Temu T, Cox J. The MaxQuant computational platform for mass spectrometry-based shotgun proteomics. Nat Protoc. 2016;11:2301\u201319.","journal-title":"Nat Protoc"},{"key":"1716_CR33","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s00281-022-00978-w","volume":"45","author":"Y Glasson","year":"2023","unstructured":"Glasson Y, Ch\u00e9peaux L-A, Dum\u00e9 A-S, Lafont V, Faget J, Bonnefoy N, et al. Single-cell high-dimensional imaging mass cytometry: one step beyond in oncology. Semin Immunopathol. 2023;45:17\u201328.","journal-title":"Semin Immunopathol"},{"key":"1716_CR34","doi-asserted-by":"publisher","first-page":"2657","DOI":"10.3389\/fimmu.2019.02657","volume":"10","author":"H Baharlou","year":"2019","unstructured":"Baharlou H, Canete NP, Cunningham AL, Harman AN, Patrick E. Mass cytometry imaging for the study of human diseases-applications and data analysis strategies. Front Immunol. 2019;10:2657.","journal-title":"Front Immunol"},{"key":"1716_CR35","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1038\/s41592-019-0582-9","volume":"16","author":"S Berg","year":"2019","unstructured":"Berg S, Kutra D, Kroeger T, Straehle CN, Kausler BX, Haubold C, et al. Ilastik: interactive machine learning for (bio)image analysis. Nat Methods. 2019;16:1226\u201332.","journal-title":"Nat Methods"},{"key":"1716_CR36","doi-asserted-by":"publisher","first-page":"3565","DOI":"10.1038\/s41596-023-00881-0","volume":"18","author":"J Windhager","year":"2023","unstructured":"Windhager J, Zanotelli VRT, Schulz D, Meyer L, Daniel M, Bodenmiller B, et al. An end-to-end workflow for multiplexed image processing and analysis. Nat Protoc. 2023;18:3565\u2013613.","journal-title":"Nat Protoc"},{"key":"1716_CR37","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41586-023-06252-9","volume":"620","author":"T Kumar","year":"2023","unstructured":"Kumar T, Nee K, Wei R, He S, Nguyen QH, Bai S, et al. A spatially resolved single-cell genomic atlas of the adult human breast. Nature. 2023;620:181\u201391.","journal-title":"Nature"},{"key":"1716_CR38","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1038\/nmeth.4391","volume":"14","author":"D Schapiro","year":"2017","unstructured":"Schapiro D, Jackson HW, Raghuraman S, Fischer JR, Zanotelli VRT, Schulz D, et al. HistoCAT: analysis of cell phenotypes and interactions in multiplex image cytometry data. Nat Methods. 2017;14:873\u20136.","journal-title":"Nat Methods"},{"key":"1716_CR39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.010","author":"Y Goltsev","year":"2018","unstructured":"Goltsev Y, Samusik N, Kennedy-Darling J, Bhate S, Hale M, Vazquez G, et al. Deep profiling of mouse splenic architecture with CODEX multiplexed imaging. Cell. 2018. https:\/\/doi.org\/10.1016\/j.cell.2018.07.010.","journal-title":"Cell"},{"key":"1716_CR40","doi-asserted-by":"publisher","unstructured":"Sch\u00fcrch CM, Bhate SS, Barlow GL, Phillips DJ, Noti L, Zlobec I, Chu P, et al. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front. Cell. 2020. https:\/\/doi.org\/10.1016\/j.cell.2020.07.005.","DOI":"10.1016\/j.cell.2020.07.005"},{"key":"1716_CR41","first-page":"314","volume":"15","author":"W Widowati","year":"2025","unstructured":"Widowati W, Nur Sabrina AH, Sutendi AF, Zahiroh FH, Wargasetia TL, Nainggolan IM, et al. M2 Macrophages-Based Immunotherapy: A New Therapeutic Approach in Liver Fibrosis. Advanced Pharmaceutical Bulletin. 2025;15:314\u201325.","journal-title":"Advanced Pharmaceutical Bulletin"},{"key":"1716_CR42","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41420-024-02247-1","volume":"10","author":"Y Jiang","year":"2024","unstructured":"Jiang Y, Cai R, Huang Y, Zhu L, Xiao L, Wang C, et al. Macrophages in organ fibrosis: from pathogenesis to therapeutic targets. Cell Death Discov. 2024;10:487.","journal-title":"Cell Death Discov"},{"key":"1716_CR43","first-page":"19","volume":"1","author":"C Abate","year":"1990","unstructured":"Abate C, Curran T. Encounters with Fos and Jun on the road to AP-1. Semin Cancer Biol. 1990;1:19\u201326.","journal-title":"Semin Cancer Biol"},{"key":"1716_CR44","doi-asserted-by":"publisher","first-page":"103488","DOI":"10.1016\/j.redox.2025.103488","volume":"80","author":"F He","year":"2025","unstructured":"He F, Du W, Liu Y, Ling Y, Xu M, Liu J, et al. Exosome-equipped TNF antisense oligodeoxynucleotide or 2-deoxy-D-glucose ameliorated nonalcoholic steatohepatitis by modulating superoxide dismutase 1 in mice. Redox Biol. 2025;80:103488.","journal-title":"Redox Biol"},{"key":"1716_CR45","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jconrel.2021.11.019","volume":"341","author":"H Li","year":"2022","unstructured":"Li H, Feng Y, Zheng X, Jia M, Mei Z, Wang Y, et al. M2-type exosomes nanoparticles for rheumatoid arthritis therapy via macrophage re-polarization. J Control Release. 2022;341:16\u201330.","journal-title":"J Control Release"},{"key":"1716_CR46","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s13287-025-04197-6","volume":"16","author":"W Jiang","year":"2025","unstructured":"Jiang W, Zeng Q, Liu C-H, Wang Y, Wang S, Chen E, et al. Huc-MSCs-derived exosomes alleviate non-alcoholic steatohepatitis by regulating macrophages polarization through miR-24-3p\/STING axis. Stem Cell Res Ther. 2025;16:74.","journal-title":"Stem Cell Res Ther"},{"key":"1716_CR47","doi-asserted-by":"publisher","first-page":"156439","DOI":"10.1016\/j.phymed.2025.156439","volume":"138","author":"M Zhao","year":"2025","unstructured":"Zhao M, He Q, Shu X, Xu R, Zhang Z, Mou Y, et al. Zhuyu pill attenuates metabolic-associated fatty liver disease by regulating macrophage polarization through TLR4 signaling pathway. Phytomedicine. 2025;138:156439.","journal-title":"Phytomedicine"},{"key":"1716_CR48","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41419-025-07376-8","volume":"16","author":"W Yang","year":"2025","unstructured":"Yang W, Yan X, Chen R, Xin X, Ge S, Zhao Y, et al. Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarization. Cell Death Dis. 2025;16:58.","journal-title":"Cell Death Dis"},{"key":"1716_CR49","doi-asserted-by":"publisher","first-page":"2579","DOI":"10.1038\/s41401-024-01389-3","volume":"45","author":"X-F Lin","year":"2024","unstructured":"Lin X-F, Cui X-N, Yang J, Jiang Y-F, Wei T-J, Xia L, et al. SGLT2 inhibitors ameliorate NAFLD in mice via downregulating PFKFB3, suppressing glycolysis and modulating macrophage polarization. Acta Pharmacol Sin. 2024;45:2579\u201397.","journal-title":"Acta Pharmacol Sin"},{"key":"1716_CR50","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/s41419-025-07574-4","volume":"16","author":"C Li","year":"2025","unstructured":"Li C, Fang L, Su X, Zhang J, Xiong H, Yu H, et al. Macrophage miR-4524a-5p\/TBP promotes \u03b2-TrCP -TIM3 complex activation and TGF\u03b2 release and aggravates NAFLD-associated fibrosis. Cell Death Dis. 2025;16:315.","journal-title":"Cell Death Dis"},{"key":"1716_CR51","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.tips.2014.09.005","volume":"35","author":"RN Rodionov","year":"2014","unstructured":"Rodionov RN, Jarzebska N, Weiss N, Lentz SR. AGXT2: a promiscuous aminotransferase. Trends Pharmacol Sci. 2014;35:575\u201382.","journal-title":"Trends Pharmacol Sci"},{"key":"1716_CR52","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/0305-0491(82)90512-0","volume":"72","author":"Y Takada","year":"1982","unstructured":"Takada Y, Noguchi T. Subcellular distribution, and physical and immunological properties of hepatic alanine: glyoxylate aminotransferase isoenzymes in different mammalian species. Comp Biochem Physiol B. 1982;72:597\u2013604.","journal-title":"Comp Biochem Physiol B"},{"key":"1716_CR53","doi-asserted-by":"publisher","first-page":"5385","DOI":"10.1074\/jbc.M109.091280","volume":"285","author":"RN Rodionov","year":"2010","unstructured":"Rodionov RN, Murry DJ, Vaulman SF, Stevens JW, Lentz SR. Human alanine-glyoxylate aminotransferase 2 lowers asymmetric dimethylarginine and protects from inhibition of nitric oxide production. J Biol Chem. 2010;285:5385\u201391.","journal-title":"J Biol Chem"},{"key":"1716_CR54","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1093\/oxfordjournals.jbchem.a122695","volume":"105","author":"H Miyajima","year":"1989","unstructured":"Miyajima H, Oda T, Ichiyama A. Induction of mitochondrial serine:pyruvate aminotransferase of rat liver by glucagon and insulin through different mechanisms. J Biochem. 1989;105:500\u20134.","journal-title":"J Biochem"},{"key":"1716_CR55","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/j.jhep.2021.04.011","volume":"75","author":"T Yoo","year":"2021","unstructured":"Yoo T, Joo SK, Kim HJ, Kim HY, Sim H, Lee J, et al. Disease-specific eQTL screening reveals an anti-fibrotic effect of AGXT2 in non-alcoholic fatty liver disease. J Hepatol. 2021;75:514\u201323.","journal-title":"J Hepatol"},{"key":"1716_CR56","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.2147\/JHC.S470250","volume":"11","author":"T Chen","year":"2024","unstructured":"Chen T, Xiang L, Zhang W, Xia Z, Chen W. AGXT2 suppresses the proliferation and dissemination of hepatocellular carcinoma cells by modulating intracellular lipid metabolism. J Hepatocell Carcinoma. 2024;11:1623\u201339.","journal-title":"J Hepatocell Carcinoma"},{"key":"1716_CR57","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1007\/s00726-021-02999-5","volume":"53","author":"AN Bogner","year":"2021","unstructured":"Bogner AN, Stiers KM, Tanner JJ. Structure, biochemistry, and gene expression patterns of the proline biosynthetic enzyme pyrroline-5-carboxylate reductase (PYCR), an emerging cancer therapy target. Amino Acids. 2021;53:1817\u201334.","journal-title":"Amino Acids"},{"key":"1716_CR58","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2022.109468","volume":"733","author":"KR Meeks","year":"2023","unstructured":"Meeks KR, Tanner JJ. Expression and kinetic characterization of PYCR3. Arch Biochem Biophys. 2023;733:109468.","journal-title":"Arch Biochem Biophys"},{"key":"1716_CR59","first-page":"12346","volume":"8","author":"W Li","year":"2015","unstructured":"Li W, You Y, Zhang X, Song Y, Xiang H, Peng X, et al. Amplification of chromosome 8q21-qter associated with the acquired paclitaxel resistance of nasopharyngeal carcinoma cells. Int J Clin Exp Pathol. 2015;8:12346\u201356.","journal-title":"Int J Clin Exp Pathol"},{"key":"1716_CR60","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s12953-024-00238-9","volume":"22","author":"N Ding","year":"2024","unstructured":"Ding N, Wang R, Wang P, Wang F. Metabolism-related proteins as biomarkers for predicting prognosis in polycystic ovary syndrome. Proteome Sci. 2024;22:14.","journal-title":"Proteome Sci"},{"key":"1716_CR61","doi-asserted-by":"publisher","first-page":"101900","DOI":"10.1016\/j.molmet.2024.101900","volume":"81","author":"MR Farook","year":"2024","unstructured":"Farook MR, Croxford Z, Morgan S, Horlock AD, Holt AK, Rees A, et al. Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer. Mol Metab. 2024;81:101900.","journal-title":"Mol Metab"},{"key":"1716_CR62","doi-asserted-by":"publisher","first-page":"736837","DOI":"10.1155\/2012\/736837","volume":"2012","author":"VI Lushchak","year":"2012","unstructured":"Lushchak VI. Glutathione homeostasis and functions: potential targets for medical interventions. J Amino Acids. 2012;2012:736837.","journal-title":"J Amino Acids"},{"key":"1716_CR63","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1093\/jn\/134.3.489","volume":"134","author":"G Wu","year":"2004","unstructured":"Wu G, Fang Y-Z, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004;134:489\u201392.","journal-title":"J Nutr"},{"key":"1716_CR64","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines13030644","author":"MT Nguyen","year":"2025","unstructured":"Nguyen MT, Lian A, Guilford FT, Venketaraman V. A literature review of glutathione therapy in ameliorating hepatic dysfunction in non-alcoholic fatty liver disease. Biomedicines. 2025. https:\/\/doi.org\/10.3390\/biomedicines13030644.","journal-title":"Biomedicines"},{"key":"1716_CR65","doi-asserted-by":"crossref","unstructured":"Leite JSM, Vilas-Boas EA, Takahashi HK, Munhoz AC, Ara\u00fajo LCC, Carvalho CR, Jr JD, et al. Liver lipid metabolism, oxidative stress, and inflammation in glutamine-supplemented ob\/ob mice. The Journal of Nutritional Biochemistry 2025;138:109842.","DOI":"10.1016\/j.jnutbio.2025.109842"},{"key":"1716_CR66","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cmet.2016.08.009","volume":"25","author":"GS Ducker","year":"2017","unstructured":"Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab. 2017;25:27\u201342.","journal-title":"Cell Metab"},{"key":"1716_CR67","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz2841","author":"O Rom","year":"2020","unstructured":"Rom O, Liu Y, Liu Z, Zhao Y, Wu J, Ghrayeb A, et al. Glycine-based treatment ameliorates NAFLD by modulating fatty acid oxidation, glutathione synthesis, and the gut microbiome. Sci Transl Med. 2020. https:\/\/doi.org\/10.1126\/scitranslmed.aaz2841.","journal-title":"Sci Transl Med"},{"key":"1716_CR68","doi-asserted-by":"publisher","first-page":"103839","DOI":"10.1016\/j.redox.2025.103839","volume":"86","author":"MN Kanaan","year":"2025","unstructured":"Kanaan MN, Karam CY, Kennedy LS, Pileggi CA, Hamilton L, Cuperlovic-Culf M, et al. Impaired xCT-mediated cystine uptake drives serine and proline metabolic reprogramming and mitochondrial fission in skeletal muscle cells. Redox Biol. 2025;86:103839.","journal-title":"Redox Biol"},{"key":"1716_CR69","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s00726-017-2490-6","volume":"50","author":"P Li","year":"2018","unstructured":"Li P, Wu G. Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth. Amino Acids. 2018;50:29\u201338.","journal-title":"Amino Acids"},{"key":"1716_CR70","doi-asserted-by":"publisher","first-page":"1357","DOI":"10.1007\/s00726-018-2611-x","volume":"50","author":"P de Paz-Lugo","year":"2018","unstructured":"de Paz-Lugo P, Lupi\u00e1\u00f1ez JA, Mel\u00e9ndez-Hevia E. High glycine concentration increases collagen synthesis by articular chondrocytes in vitro: acute glycine deficiency could be an important cause of osteoarthritis. Amino Acids. 2018;50:1357\u201365.","journal-title":"Amino Acids"},{"key":"1716_CR71","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1111\/j.1346-8138.2010.00827.x","volume":"37","author":"H Ohara","year":"2010","unstructured":"Ohara H, Ichikawa S, Matsumoto H, Akiyama M, Fujimoto N, Kobayashi T, et al. Collagen-derived dipeptide, proline-hydroxyproline, stimulates cell proliferation and hyaluronic acid synthesis in cultured human dermal fibroblasts. J Dermatol. 2010;37:330\u20138.","journal-title":"J Dermatol"},{"key":"1716_CR72","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/180243a0","volume":"180","author":"DA Hall","year":"1957","unstructured":"Hall DA, Reed R. Hydroxyproline and thermal stability of collagen. Nature. 1957;180:243.","journal-title":"Nature"},{"key":"1716_CR73","doi-asserted-by":"publisher","unstructured":"Alves A, Bassot A, Bulteau A-L, Pirola L, Morio B. Glycine metabolism and its alterations in obesity and metabolic diseases. Nutrients. 2019. https:\/\/doi.org\/10.3390\/nu11061356.","DOI":"10.3390\/nu11061356"},{"key":"1716_CR74","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.diabres.2017.07.023","volume":"132","author":"AP Okekunle","year":"2017","unstructured":"Okekunle AP, Li Y, Liu L, Du S, Wu X, Chen Y, et al. Abnormal circulating amino acid profiles in multiple metabolic disorders. Diabetes Res Clin Pract. 2017;132:45\u201358.","journal-title":"Diabetes Res Clin Pract"},{"key":"1716_CR75","doi-asserted-by":"publisher","first-page":"80223","DOI":"10.18632\/oncotarget.12831","volume":"7","author":"X Zhou","year":"2016","unstructured":"Zhou X, Han D, Xu R, Wu H, Qu C, Wang F, et al. Glycine protects against high sucrose and high fat-induced non-alcoholic steatohepatitis in rats. Oncotarget. 2016;7:80223\u201337.","journal-title":"Oncotarget"},{"key":"1716_CR76","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.jare.2025.05.029","volume":"80","author":"R Zhou","year":"2025","unstructured":"Zhou R, Zhang X, Liu X, Huang R, Wang Y, Xia D, et al. Association between dietary amino acid intake and the risk of metabolic dysfunction-associated steatotic liver disease. J Adv Res. 2025;80:893\u2013903.","journal-title":"J Adv Res"},{"key":"1716_CR77","volume":"5","author":"A De Masi","year":"2023","unstructured":"De Masi A, Li X, Lee D, Jeon J, Wang Q, Baek S, et al. Cyclo(His-Pro): a further step in the management of steatohepatitis. JHEP Rep Innov Hepatol. 2023;5:100815.","journal-title":"JHEP Rep Innov Hepatol"},{"key":"1716_CR78","doi-asserted-by":"publisher","unstructured":"Zhang S, Chen X, Jin E, Wang A, Chen T, Zhang X, Zhu J, et al. The GSA family in 2025: a broadened sharing platform for multi-omics and multimodal data. Genom Proteomics Bioinformatics. 2025. https:\/\/doi.org\/10.1101\/2025.03.31.646270.","DOI":"10.1101\/2025.03.31.646270"},{"key":"1716_CR79","doi-asserted-by":"publisher","first-page":"D30","DOI":"10.1093\/nar\/gkae978","volume":"53","author":"Database Resources of the National Genomics Data Center","year":"2025","unstructured":"Database Resources of the National Genomics Data Center. China National Center for Bioinformation in 2025. Nucleic Acids Res. 2025;53:D30\u201344.","journal-title":"Nucleic Acids Res"},{"key":"1716_CR80","unstructured":"Lv TS, Zhou XQ. Multi-omics and spatial proteomic profiling reveal novel AGXT2- PYCR3- macrophages and their phenotypes in metabolic dysfunction-associated steatotic liver disease [Proteomic Data]. OMIX (Accession No. OMIX018181). https:\/\/ngdc.cncb.ac.cn\/omix."}],"container-title":["Genome Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13073-026-01716-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-026-01716-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13073-026-01716-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T15:03:00Z","timestamp":1793631780000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13073-026-01716-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":80,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1716"],"URL":"https:\/\/doi.org\/10.1186\/s13073-026-01716-9","relation":{},"ISSN":["1756-994X"],"issn-type":[{"value":"1756-994X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]},"assertion":[{"value":"21 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The use of clinical specimens in this study was approved by the Ethics Committee of Jiangsu Province Hospital of Chinese Medicine (Name: Construction and Management of Metabolic Steatotic Liver Biobank, ID: 2022NL-122\u201302, Time: 2022\u201307-22, Version No.: 2.0).This study was conducted in accordance with the principles of the Declaration of Helsinki. All participants were fully informed of the relevant surgical risks prior to specimen collection, and informed consent was obtained from each patient before pathological tissue sampling. Notably, the acquisition of tissue samples did not interfere with routine clinical pathological diagnosis and treatment.All names of metabolic-related steatotic liver disease in this paper will be referred to as MASLD to avoid stigmatization of patients.In addition, this study did not involve animal experiments.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable. No individual identifiable information, clinical images, or personal patient data are contained within this manuscript. All experimental and clinical data are presented in aggregated and anonymized forms, and no specific informed consent for publication is needed.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"169"}}