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However, current clinical and research frameworks rely primarily on static, histology-defined stages that fail to capture the continuous nature of disease progression. Here, we present a data-driven framework that reconstructs MASLD progression as a continuous molecular trajectory from cross-sectional liver transcriptomic profiles. By positioning patients along this trajectory, we move beyond conventional stage-based classifications and resolve the ordered activation of regulatory programmes, signalling pathways and cellular remodelling processes underlying disease progression. To enable non-invasive patient stratification, we integrate the inferred molecular trajectory with paired liver-plasma proteomics data and identify a 57-gene plasma-accessible biomarker panel that accurately predicts advanced fibrosis and continuously positions patients along the disease trajectory across independent cohorts, outperforming established non-invasive clinical scores. Together, this work establishes a generalizable trajectory-based framework for understanding MASLD pathophysiology and provides a foundation for mechanistically informed biomarker discovery, precision staging and stage-aware therapeutic prioritization.<\/jats:p>","DOI":"10.1038\/s42255-026-01543-7","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T09:02:53Z","timestamp":1784019773000},"page":"1545-1562","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A data-driven framework reconstructs the molecular continuum of human MASLD progression"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7408-5284","authenticated-orcid":false,"given":"Ioannis","family":"Kamzolas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0659-7245","authenticated-orcid":false,"given":"Thodoris","family":"Koutsandreas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie George","family":"Barker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Vathrakokoili Pournara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4063-6041","authenticated-orcid":false,"given":"Harry","family":"Weston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4109-3421","authenticated-orcid":false,"given":"Naoto","family":"Fujiwara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9430-1426","authenticated-orcid":false,"given":"Yujin","family":"Hoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9518-0088","authenticated-orcid":false,"given":"Quentin M.","family":"Anstee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Vacca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7270-5470","authenticated-orcid":false,"given":"Irene","family":"Papatheodorou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4220-9577","authenticated-orcid":false,"given":"Antonio","family":"Vidal-Puig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8294-2995","authenticated-orcid":false,"given":"Evangelia","family":"Petsalaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"1543_CR1","doi-asserted-by":"publisher","first-page":"197","DOI":"10.7570\/jomes23052","volume":"32","author":"WK Chan","year":"2023","unstructured":"Chan, W. 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