{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T11:42:12Z","timestamp":1778672532303,"version":"3.51.4"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"China and Germany jointly develop a new generation of stem cell therapy technology for hepatic fibrosis\/cirrhosis","award":["23ZDWA003"],"award-info":[{"award-number":["23ZDWA003"]}]},{"name":"2022 Gansu Province Traditional Chinese Medicine Industry Innovation Consortium Project: Clinical Evaluation Study of Shugan Lidan Granules","award":["22ZD6FA021-4"],"award-info":[{"award-number":["22ZD6FA021-4"]}]},{"name":"2023 Gansu Province Science and Technology Plan Project: Experimental Study on the Effect of Different Routes of HUCB-MSC Derived Exosomes on Liver Regeneration Rate after Hepatectomy","award":["23YFFA0034"],"award-info":[{"award-number":["23YFFA0034"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly linked to systemic metabolic disturbances and features a lipid-driven cascade that promotes hepatic inflammation and fibrosis. Choline insufficiency contributes to disease advancement by altering phospholipid turnover and redox homeostasis; however, its spatial and temporal regulatory roles throughout MASLD progression remain insufficiently defined. A 10-week high-fat, choline-deficient (HFCD) mouse model was established, and liver pathology was evaluated at weeks 6, 8, and 10. Time-resolved assessments combined untargeted metabolomics, magnetic resonance imaging\u2013proton density fat fraction (MRI-PDFF), serum biochemistry, histological staining, immunofluorescence, and transmission electron microscopy to characterize dynamic alterations in lipid metabolism, redox status, inflammation, and fibrogenesis. The HFCD diet produced a clear temporal sequence of liver injury. Steatosis, phosphatidylcholine depletion, and early antioxidant loss appeared by week 6. By week 8, mitochondrial structural damage and pronounced cytokine elevation were evident. At week 10, collagen deposition and \u03b1-SMA activation signaled fibrotic progression. Metabolomics indicated significant disruptions in pathways related to ATP-binding cassette (ABC) transporters, one-carbon metabolism, and the tricarboxylic acid (TCA) cycle. Using integrated analytical strategies, this study suggests that choline deficiency may be associated with a time-dependent pathological cascade in MASLD, beginning with phospholipid destabilization and extending to altered mitochondria\u2013endoplasmic reticulum crosstalk at mitochondria-associated membranes, alongside amplified oxidative\u2013inflammatory responses, which collectively may contribute to progressive fibrogenesis as the disease advances.<\/jats:p>","DOI":"10.3390\/antiox15010110","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:26:36Z","timestamp":1768465596000},"page":"110","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Choline Deficiency Drives the Inflammation\u2013Fibrosis Cascade: A Spatiotemporal Atlas of Hepatic Injury from Weeks 6 to 10"],"prefix":"10.3390","volume":"15","author":[{"given":"Shang","family":"Li","sequence":"first","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohong","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Zhao","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Axi","family":"Shi","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingmin","family":"Dong","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changpeng","family":"Chai","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojing","family":"Song","sequence":"additional","affiliation":[{"name":"Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhui","family":"Wei","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"},{"name":"School of Pharmacy, Lanzhou University, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xun","family":"Li","sequence":"additional","affiliation":[{"name":"The First School of Clinical Medicine, Lanzhou University, Lanzhou 730000, China"},{"name":"Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, China"},{"name":"Medical Engineering Center for Liver Repair and Regeneration of Gansu Province, Lanzhou 730000, China"},{"name":"Hepatopancreatobiliary Surgery Institute of Gansu Province, Lanzhou 730000, China"},{"name":"Clinical Research Center for General Surgery of Gansu Province, Lanzhou 730000, China"},{"name":"Innovation Center for Advanced Particle and Nuclear Medicine Technologies, The First Hospital of Lanzhou University, Lanzhou 730000, China"},{"name":"Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1136\/gutjnl-2023-330595","article-title":"MASLD: A systemic metabolic disorder with cardiovascular and malignant complications","volume":"73","author":"Targher","year":"2024","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1007\/s13679-024-00574-z","article-title":"Non-invasive Scores and Serum Biomarkers for Fatty Liver in the Era of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): A Comprehensive Review from NAFLD to MAFLD and MASLD","volume":"13","author":"Abdelhameed","year":"2024","journal-title":"Curr. Obes. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"79","author":"Rinella","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.tem.2024.02.012","article-title":"Evolving liver disease insights from NAFLD to MASLD","volume":"35","author":"Fan","year":"2024","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s11892-024-01558-y","article-title":"NAFLD No More: A Review of Current Guidelines in the Diagnosis and Evaluation of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)","volume":"25","author":"Kaylan","year":"2024","journal-title":"Curr. Diabetes Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e155","DOI":"10.1016\/j.jhep.2024.02.021","article-title":"The transition from NAFLD to MASLD and its impact on clinical practice and outcomes","volume":"81","author":"Lu","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1016\/S2468-1253(24)00193-6","article-title":"Natural history and progression of metabolic dysfunction-associated steatotic liver disease","volume":"9","author":"Hagstrom","year":"2024","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/s41575-020-00381-6","article-title":"Global epidemiology of NAFLD-related HCC: Trends, predictions, risk factors and prevention","volume":"18","author":"Huang","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1016\/j.cgh.2024.03.006","article-title":"The Global Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among Patients With Type 2 Diabetes","volume":"22","author":"Younossi","year":"2024","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Beygi, M., Ahi, S., Zolghadri, S., and Stanek, A. (2024). Management of Metabolic-Associated Fatty Liver Disease\/Metabolic Dysfunction-Associated Steatotic Liver Disease: From Medication Therapy to Nutritional Interventions. Nutrients, 16.","DOI":"10.3390\/nu16142220"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1186\/s12933-022-01697-0","article-title":"Metabolic dysfunction-associated fatty liver disease and implications for cardiovascular risk and disease prevention","volume":"21","author":"Zhou","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tian, Y., Hong, X., Xie, Y., Guo, Z., and Yu, Q. (2023). 17beta-Estradiol (E(2)) Upregulates the ERalpha\/SIRT1\/PGC-1alpha Signaling Pathway and Protects Mitochondrial Function to Prevent Bilateral Oophorectomy (OVX)-Induced Nonalcoholic Fatty Liver Disease (NAFLD). Antioxidants, 12.","DOI":"10.3390\/antiox12122100"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1007\/s12072-024-10701-6","article-title":"Telomere length and mortality in lean MAFLD: The other face of metabolic adaptation","volume":"18","author":"Alarabi","year":"2024","journal-title":"Hepatol. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"939","DOI":"10.14218\/JCTH.2022.00067","article-title":"Reactive Oxygen Species and Oxidative Stress in the Pathogenesis of MAFLD","volume":"10","author":"Clare","year":"2022","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1080\/15548627.2021.1895658","article-title":"The menage a trois of autophagy, lipid droplets and liver disease","volume":"18","author":"Hunter","year":"2022","journal-title":"Autophagy"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Bernhard, W., Bockmann, K.A., Minarski, M., Wiechers, C., Busch, A., Bach, D., Poets, C.F., and Franz, A.R. (2024). Evidence and Perspectives for Choline Supplementation during Parenteral Nutrition-A Narrative Review. Nutrients, 16.","DOI":"10.3390\/nu16121873"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1161\/CIRCRESAHA.123.323284","article-title":"VLDL Biogenesis and Secretion: It Takes a Village","volume":"134","author":"Ginsberg","year":"2024","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kim, M.J., Park, Y.R., Jang, G., Han, Y.K., Ishii, I., Jang, S.Y., and Park, K.M. (Antioxid. Redox Signal., 2025). Cystathionine gamma-Lyase Protects Against Choline-Deficient High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease Through the Cysteine-Glutathione Axis in Mice, Antioxid. Redox Signal., Online ahead of print.","DOI":"10.1177\/15230864251377735"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1007\/s13668-024-00521-3","article-title":"The Interplay Between Dietary Choline and Cardiometabolic Disorders: A Review of Current Evidence","volume":"13","author":"Vallianou","year":"2024","journal-title":"Curr. Nutr. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1194\/jlr.M700181-JLR200","article-title":"Polyunsaturated fat in the methionine-choline-deficient diet influences hepatic inflammation but not hepatocellular injury","volume":"48","author":"Lee","year":"2007","journal-title":"J. Lipid Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.freeradbiomed.2022.08.037","article-title":"Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate experimental non-alcoholic steatohepatitis via Nrf2\/NQO-1 pathway","volume":"192","author":"Kang","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_22","first-page":"e0716","article-title":"VLDL lipidomics reveals hepatocellular lipidome changes in metabolic dysfunction-associated steatotic liver disease","volume":"9","author":"Yalcin","year":"2025","journal-title":"Hepatol. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103038","DOI":"10.1016\/j.fochx.2025.103038","article-title":"Identification of lipids and proteins associated with different heat treatments in sheep milk based on lipidomics and proteomics","volume":"31","author":"Zhu","year":"2025","journal-title":"Food Chem. X"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1002\/ptr.8010","article-title":"Baicalin attenuated metabolic dysfunction-associated fatty liver disease by suppressing oxidative stress and inflammation via the p62-Keap1-Nrf2 signalling pathway in db\/db mice","volume":"39","author":"Liu","year":"2025","journal-title":"Phytother. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115724","DOI":"10.1016\/j.biopha.2023.115724","article-title":"Bioactive dipeptides mitigate high-fat and high-fructose corn syrup diet-induced metabolic-associated fatty liver disease via upregulation of Nrf2\/HO-1 expressions in C57BL\/6J mice","volume":"168","author":"Wayal","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/j.jhep.2022.06.012","article-title":"Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease-novel insights into cellular communication circuits","volume":"77","author":"Peiseler","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102743","DOI":"10.1016\/j.ceca.2023.102743","article-title":"The ER-mitochondria interface, where Ca2+ and cell death meet","volume":"112","author":"Kerkhofs","year":"2023","journal-title":"Cell Calcium"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e202206008","DOI":"10.1083\/jcb.202206008","article-title":"PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration","volume":"222","author":"Sassano","year":"2023","journal-title":"J. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/s41418-024-01414-2","article-title":"AKAP1\/PKA-mediated GRP75 phosphorylation at mitochondria-associated endoplasmic reticulum membranes protects cancer cells against ferroptosis","volume":"32","author":"Liu","year":"2025","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1016\/j.cmet.2023.07.002","article-title":"Hepatic levels of S-adenosylmethionine regulate the adaptive response to fasting","volume":"35","author":"Mosca","year":"2023","journal-title":"Cell Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e1325","DOI":"10.1002\/ctm2.1325","article-title":"Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis-induced formation of neutrophil extracellular traps","volume":"13","author":"Lv","year":"2023","journal-title":"Clin. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3898","DOI":"10.1039\/D0FO02736G","article-title":"Hesperetin ameliorates hepatic oxidative stress and inflammation via the PI3K\/AKT-Nrf2-ARE pathway in oleic acid-induced HepG2 cells and a rat model of high-fat diet-induced NAFLD","volume":"12","author":"Li","year":"2021","journal-title":"Food Funct."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jhep.2022.02.031","article-title":"Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis","volume":"77","author":"Wang","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107352","DOI":"10.1016\/j.ultsonch.2025.107352","article-title":"Ultrasound-driven ROS-scavenging nanobubbles for synergistic NASH treatment via FXR activation","volume":"118","author":"Lin","year":"2025","journal-title":"Ultrason. Sonochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"103159","DOI":"10.1016\/j.redox.2024.103159","article-title":"SLC7A11-ROS\/alphaKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression","volume":"72","author":"Lv","year":"2024","journal-title":"Redox Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4579","DOI":"10.7150\/thno.108280","article-title":"ROS-responsive MnO(2) mesoporous hydrogel to modulate liver-muscle crosstalk and mitigate NAFLD-associated sarcopenia via exosomal miR-582-5p delivery","volume":"15","author":"Jiang","year":"2025","journal-title":"Theranostics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1186\/s12967-024-04942-0","article-title":"ACACA reduces lipid accumulation through dual regulation of lipid metabolism and mitochondrial function via AMPK- PPARalpha- CPT1A axis","volume":"22","author":"Dong","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1002\/hep.32569","article-title":"Lipocalin-2 activates hepatic stellate cells and promotes nonalcoholic steatohepatitis in high-fat diet-fed Ob\/Ob mice","volume":"77","author":"Kim","year":"2023","journal-title":"Hepatology"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Pi, D., Liang, Z., Pan, J., Zhen, J., Zheng, C., Fan, W., Song, Q., Pan, M., Yang, Q., and Zhang, Y. (2024). Tanshinone IIA Inhibits the Endoplasmic Reticulum Stress-Induced Unfolded Protein Response by Activating the PPARalpha\/FGF21 Axis to Ameliorate Nonalcoholic Steatohepatitis. Antioxidants, 13.","DOI":"10.3390\/antiox13091026"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"105482","DOI":"10.1016\/j.ebiom.2024.105482","article-title":"Microbiome and metabolomics reveal the effect of gut microbiota on liver regeneration of fatty liver disease","volume":"111","author":"Hu","year":"2025","journal-title":"EBioMedicine"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13039","DOI":"10.1021\/acs.jafc.3c09132","article-title":"Elevated PINK1\/Parkin-Dependent Mitophagy and Boosted Mitochondrial Function Mediate Protection of HepG2 Cells from Excess Palmitic Acid by Hesperetin","volume":"72","author":"Li","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e171267","DOI":"10.1172\/JCI171267","article-title":"Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition","volume":"133","author":"Chin","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S0025-6196(24)00530-5","article-title":"Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease","volume":"55","author":"Ludwig","year":"1980","journal-title":"Mayo Clin. Proc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","article-title":"MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease","volume":"158","author":"Eslam","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.3350\/cmh.2022.0367","article-title":"MAFLD: How is it different from NAFLD?","volume":"29","author":"Gofton","year":"2023","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s11306-007-0082-2","article-title":"Proposed minimum reporting standards for chemical analysis Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI)","volume":"3","author":"Sumner","year":"2007","journal-title":"Metabolomics"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/1\/110\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:34:44Z","timestamp":1768469684000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/1\/110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,15]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["antiox15010110"],"URL":"https:\/\/doi.org\/10.3390\/antiox15010110","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,15]]}}}