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HCC surveillance is currently restricted to patients with cirrhosis, leaving those without cirrhosis, who present with more advanced disease and poorer outcomes without adequate risk stratification tools. This study compared lipid profiles across MAFLD and MAFLD-related HCC (MAFLD-HCC) patients, with and without cirrhosis, to characterise metabolic dysregulation underlying non-cirrhotic MAFLD-HCC (ncMAFLD-HCC). Plasma and liver lipidomic profiles were obtained from 221 patients (140 MAFLD, 66 cirrhotic MAFLD-HCC (cMAFLD-HCC), and 15 ncMAFLD-HCC) using untargeted liquid chromatography mass spectrometry. Univariate, multivariable and enrichment analyses were performed for statistically determining the lipid profile difference between the groups. Seventy percent of lipid classes were more abundant in MAFLD than in ncMAFLD-HCC and cMAFLD-HCC. Multivariate analysis revealed distinct lipid profiles across the three groups in both plasma and liver. Over 100 lipid species including diglyceride (DAG), sphingomyelin (SM), triglyceride (TG), dihydroceramide (DHCer), and linoleic acid derivatives were differentially expressed in ncMAFLD-HCC versus MAFLD, with enrichment in pathways such as glycerolipid metabolism, G-protein signalling, MAPK signalling, EGFR-TKI resistance pathway, implicated in HCC development. ncMAFLD-HCC exhibits a distinct lipid signature, offering preliminary mechanistic insight and a foundation for non-invasive biomarker development.<\/jats:p>","DOI":"10.3390\/ijms27136060","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:43:14Z","timestamp":1783345394000},"page":"6060","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Plasma and Tissue Lipid Profiling Demonstrates a Distinctive Metabolic Profile in MAFLD-Associated Non-Cirrhotic Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0942-1700","authenticated-orcid":false,"given":"Fatema","family":"Safri","sequence":"first","affiliation":[{"name":"Storr Liver Centre, The Westmead Institute for Medical Research, Westmead, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Pickford","sequence":"additional","affiliation":[{"name":"Bioanalytical Mass Spectrometry Facility, The University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yikun","family":"Xu","sequence":"additional","affiliation":[{"name":"Storr Liver Centre, The Westmead Institute for Medical Research, Westmead, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Yang","sequence":"additional","affiliation":[{"name":"Storr Liver Centre, The Westmead Institute for Medical Research, Westmead, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0237-9523","authenticated-orcid":false,"given":"Romario","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Storr Liver Centre, The Westmead Institute for Medical Research, Westmead, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2050, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Yuen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2050, Australia"},{"name":"Department of Upper GI and HPB Surgery, Westmead Hospital, Westmead, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Lam","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2050, Australia"},{"name":"Department of Upper GI and HPB Surgery, Westmead Hospital, Westmead, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0888-4499","authenticated-orcid":false,"given":"Christopher","family":"Nahm","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2050, Australia"},{"name":"Department of Upper GI and HPB Surgery, Westmead Hospital, Westmead, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1327-9189","authenticated-orcid":false,"given":"Tony","family":"Pang","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2050, Australia"},{"name":"Department of Upper GI and HPB Surgery, Westmead Hospital, Westmead, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8421-5476","authenticated-orcid":false,"given":"Jacob","family":"George","sequence":"additional","affiliation":[{"name":"Storr Liver Centre, The Westmead Institute for Medical Research, Westmead, Sydney, NSW 2145, Australia"},{"name":"Faculty of Medicine and Health Sciences, The University of Sydney, Sydney, NSW 2050, 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