{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:07:19Z","timestamp":1785406039823,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Oxidative stress plays a crucial role in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Recently, cardiometabolic factors (CMFs) have become essential components of MASLD diagnosis. However, the extent to which individual CMFs contribute to metabolomic alterations in MASLD remains unclear. We aimed to identify associations between CMFs and metabolite levels in patients with MASLD. Serum samples from 31 patients with MASLD and 21 patients without MASLD were subjected to non-targeted metabolomic analysis using liquid chromatography\u2013mass spectrometry. We identified 35 metabolites whose serum levels differed between the non-MASLD and MASLD groups. Of these, 22 metabolites were annotated, including sphingomyelins, phosphatidylcholines, phosphatidylethanolamine, lysophosphatidylcholines, lysophosphatidylethanolamine, plasmalogens, amino acids, a bile acid, and a phenolic compound. Distinct associations were observed between CMFs and metabolite alterations, including obesity and higher glutamic acid levels, diabetes and higher SM(d36:0) and SM(d38:0) levels, and hypertension and lower LPC(18:1) and LPC(18:2) levels. Although several altered metabolites were linked to oxidative stress-related pathways, direct oxidative stress biomarkers were not measured. Thus, the relationship between these metabolite alterations and redox imbalance remains hypothetical and requires further investigation. However, the findings in the present study provide insight into the metabolic mechanisms linking cardiometabolic dysfunction and may facilitate biomarker discovery.<\/jats:p>","DOI":"10.3390\/antiox15080950","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:32:13Z","timestamp":1785403933000},"page":"950","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiometabolic Factor-Specific Metabolic Signatures in Metabolic Dysfunction-Associated Steatotic Liver Disease: Insights from Non-Targeted Metabolomics"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4265-9949","authenticated-orcid":false,"given":"Keigo","family":"Misawa","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8036-6544","authenticated-orcid":false,"given":"Kouichi","family":"Miura","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Aizawa","sequence":"additional","affiliation":[{"name":"Department of Translational Research, Clinical Research Center, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan"},{"name":"Clinical Pharmacology Center, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiko","family":"Ueki","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masako","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1320-1165","authenticated-orcid":false,"given":"Hitoshi","family":"Osaka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0160-432X","authenticated-orcid":false,"given":"Tomonori","family":"Yano","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke 329-0498, Tochigi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.3350\/cmh.2024.0431","article-title":"Epidemiology of metabolic dysfunction-associated steatotic liver disease","volume":"31","author":"Younossi","year":"2025","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1016\/j.numecd.2024.05.018","article-title":"Impacts of cardiometabolic risk factors and alcohol consumption on all-cause mortality among MASLD and its subgroups","volume":"34","author":"Li","year":"2024","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1111\/hepr.13938","article-title":"Agile 3+ and Agile 4, noninvasive tests for liver fibrosis, are excellent formulae to predict liver-related events in nonalcoholic fatty liver disease","volume":"53","author":"Miura","year":"2023","journal-title":"Hepatol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1002\/hep.27368","article-title":"Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up","volume":"61","author":"Ekstedt","year":"2015","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1111\/liv.13973","article-title":"Cardiovascular risk factors in non-alcoholic fatty liver disease","volume":"39","author":"Hagstrom","year":"2019","journal-title":"Liver Int."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Li, B., Fu, Y., Xi, H., Liu, S., Zhao, W., Li, P., Fan, W., Wang, D., and Sun, S. (2023). Untargeted Metabolomics Using UHPLC-HRMS Reveals Metabolic Changes of Fresh-Cut Potato during Browning Process. Molecules, 28.","DOI":"10.3390\/molecules28083375"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.trac.2019.05.030","article-title":"Mass Spectrometry-Based Non-targeted Metabolic Profiling for Disease Detection: Recent Developments","volume":"118","author":"Zang","year":"2019","journal-title":"TrAC Trends Anal. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1210\/clinem\/dgz240","article-title":"Metabolomics Signatures in Type 2 Diabetes: A Systematic Review and Integrative Analysis","volume":"105","author":"Sun","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Aderemi, A.V., Ayeleso, A.O., Oyedapo, O.O., and Mukwevho, E. (2021). Metabolomics: A Scoping Review of Its Role as a Tool for Disease Biomarker Discovery in Selected Non-Communicable Diseases. Metabolites, 11.","DOI":"10.3390\/metabo11070418"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100477","DOI":"10.1016\/j.jhepr.2022.100477","article-title":"Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease","volume":"4","author":"McGlinchey","year":"2022","journal-title":"JHEP Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.jhep.2021.04.013","article-title":"Hepatic lipidomic remodeling in severe obesity manifests with steatosis and does not evolve with non-alcoholic steatohepatitis","volume":"75","author":"Ooi","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nmeth.3393","article-title":"MS-DIAL: Data-independent MS\/MS deconvolution for comprehensive metabolome analysis","volume":"12","author":"Tsugawa","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7946","DOI":"10.1021\/acs.analchem.6b00770","article-title":"Hydrogen Rearrangement Rules: Computational MS\/MS Fragmentation and Structure Elucidation Using MS-FINDER Software","volume":"88","author":"Tsugawa","year":"2016","journal-title":"Anal. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ogiso, H., Miura, K., Nagai, R., Osaka, H., and Aizawa, K. (2024). Non-Targeted Metabolomics Reveal Apomorphine\u2019s Therapeutic Effects and Lysophospholipid Alterations in Steatohepatitis. Antioxidants, 13.","DOI":"10.3390\/antiox13111293"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Jacob, M., Nimer, R.M., Alabdaljabar, M.S., Sabi, E.M., Al-Ansari, M.M., Housien, M., Sumaily, K.M., Dahabiyeh, L.A., and Rahman, A.M.A. (2022). Metabolomics Profiling of Nephrotic Syndrome towards Biomarker Discovery. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012614"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Saigusa, D., Okamura, Y., Motoike, I.N., Katoh, Y., Kurosawa, Y., Saijyo, R., Koshiba, S., Yasuda, J., Motohashi, H., and Sugawara, J. (2016). Establishment of Protocols for Global Metabolomics by LC-MS for Biomarker Discovery. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0160555"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ramabulana, A.T., Petras, D., Madala, N.E., and Tugizimana, F. (2021). Metabolomics and Molecular Networking to Characterize the Chemical Space of Four Momordica Plant Species. Metabolites, 11.","DOI":"10.3390\/metabo11110763"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Im, S.S., Park, H.Y., Shon, J.C., Chung, I.-S., Cho, H.C., Liu, K.-H., and Song, D.-K. (2019). Plasma sphingomyelins increase in pre-diabetic Korean men with abdominal obesity. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0213285"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1111\/apt.16066","article-title":"Circulating lipidomic alterations in obese and non-obese subjects with non-alcoholic fatty liver disease","volume":"52","author":"Jung","year":"2020","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.clinbiochem.2016.05.016","article-title":"Serum metabonomics of NAFLD plus T2DM based on liquid chromatography-mass spectrometry","volume":"49","author":"Chen","year":"2016","journal-title":"Clin. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.metabol.2010.03.006","article-title":"Plasma metabolomic profile in nonalcoholic fatty liver disease","volume":"60","author":"Kalhan","year":"2011","journal-title":"Metabolism"},{"key":"ref_23","first-page":"70","article-title":"Glutamate and obesity\u2014What is the link?","volume":"27","author":"Chaouche","year":"2024","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1016\/j.cgh.2016.05.046","article-title":"Noninvasive Detection of Nonalcoholic Steatohepatitis Using Clinical Markers and Circulating Levels of Lipids and Metabolites","volume":"14","author":"Zhou","year":"2016","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1002\/hep.23229","article-title":"The plasma lipidomic signature of nonalcoholic steatohepatitis","volume":"50","author":"Puri","year":"2009","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hammad, S.M., and Lopes-Virella, M.F. (2023). Circulating Sphingolipids in Insulin Resistance, Diabetes and Associated Complications. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202308.1042.v1"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Tiwari-Heckler, S., Gan-Schreier, H., Stremmel, W., Chamulitrat, W., and Pathil, A. (2018). Circulating Phospholipid Patterns in NAFLD Patients Associated with a Combination of Metabolic Risk Factors. Nutrients, 10.","DOI":"10.3390\/nu10050649"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1007\/s11695-008-9521-z","article-title":"Serum phenylalanine concentration as a marker of liver function in obese patients before and after bariatric surgery","volume":"19","author":"Swierczynski","year":"2009","journal-title":"Obes. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1186\/s10020-025-01303-5","article-title":"L-Phenylalanine promotes liver steatosis by inhibiting BNIP3-mediated mitophagy","volume":"31","author":"Sun","year":"2025","journal-title":"Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Hasegawa, T., Iino, C., Endo, T., Mikami, K., Kimura, M., Sawada, N., Nakaji, S., and Fukuda, S. (2020). Changed Amino Acids in NAFLD and Liver Fibrosis: A Large Cross-Sectional Study without Influence of Insulin Resistance. Nutrients, 12.","DOI":"10.20944\/preprints202005.0127.v1"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/apt.15035","article-title":"Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD","volume":"49","author":"Caussy","year":"2019","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1161\/CIRCGENETICS.114.000606","article-title":"High-dose simvastatin exhibits enhanced lipid-lowering effects relative to simvastatin\/ezetimibe combination therapy","volume":"7","author":"Snowden","year":"2014","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.atherosclerosis.2007.02.012","article-title":"Lysophosphatidylcholine contents in plasma LDL in patients with type 2 diabetes mellitus: Relation with lipoprotein-associated phospholipase A2 and effects of simvastatin treatment","volume":"196","author":"Iwase","year":"2008","journal-title":"Atherosclerosis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"117443","DOI":"10.1016\/j.lfs.2020.117443","article-title":"The mechanisms of lysophosphatidylcholine in the development of diseases","volume":"247","author":"Liu","year":"2020","journal-title":"Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Miura, K., Arai, N., Goka, R., Morimoto, N., Watanabe, S., Isoda, N., Yamamoto, H., and Kotani, K. (2021). Oxidized High-Density Lipoprotein Shows a Stepwise Increase as Fibrosis Progresses in Patients with Nonalcoholic Fatty Liver Disease. Antioxidants, 10.","DOI":"10.3390\/antiox10020239"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1097\/HEP.0000000000000375","article-title":"Membrane phospholipid remodeling modulates nonalcoholic steatohepatitis progression by regulating mitochondrial homeostasis","volume":"79","author":"Tian","year":"2024","journal-title":"Hepatology"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Wang, F. (2026). Targeting ferroptosis to halt MASLD and MASH. Trends Endocrinol. Metab.","DOI":"10.1016\/j.tem.2026.01.007"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1042\/BCJ20240445","article-title":"Loss of peroxiredoxin 6 alters lipid composition and distribution resulting in increased sensitivity to ferroptosis","volume":"481","author":"Lagal","year":"2024","journal-title":"Biochem. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101091","DOI":"10.1016\/j.jlr.2026.101091","article-title":"Phospholipid remodeling as a key regulator of ferroptosis","volume":"67","author":"Shingaki","year":"2026","journal-title":"J. Lipid Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Rochette, L., Dogon, G., Rigal, E., Zeller, M., Cottin, Y., and Vergely, C. (2022). Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010449"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/8\/950\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:44:32Z","timestamp":1785404672000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/8\/950"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["antiox15080950"],"URL":"https:\/\/doi.org\/10.3390\/antiox15080950","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}