{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:08:19Z","timestamp":1788786499675,"version":"build-2803163510"},"reference-count":66,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:00:00Z","timestamp":1788566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Metabolic dysfunction-associated steatohepatitis (MASH) progresses through macrophage activation and hepatic stellate cell (HSC)-driven fibrogenesis. As cell-level single-cell discoveries often suffer from pseudoreplication and fail to replicate across cohorts, in this study we critically re-evaluated human liver single-nucleus RNA-sequencing data using a rigorous per-donor statistical framework to dissociate invariant biological signals from technical artifacts. Macrophage and HSC compartments from dataset GSE202379 were profiled across clinical stages (healthy, metabolic dysfunction-associated steatotic liver disease, MASH). Cell-level statistics were aggregated into per-donor metrics, and continuous phenotypic shifts evaluated via the Jonckheere\u2013Terpstra (JT) trend test. Key findings were tested for cross-cohort reproducibility in two independent cohorts (GSE136103 and GSE244832). A 249-gene scar-associated macrophage (SAMac) program showed reproducible, stage-dependent expansion in the discovery cohort (per-donor Jonckheere\u2013Terpstra trend across the disease-only spectrum, MASLD to advanced MASH, z = 2.23, p = 0.026 [primary]; z = 2.74, p = 0.006 across all four stages including the healthy baseline) and directional replication in external data. Cell\u2013cell communication analysis replicated the receptor-side topology of a conserved macrophage-to-HSC PDGF axis in both external cohorts and the ligand-driven PDGFC\u2192PDGFRB edge in the external snRNA-seq cohort (GSE244832), with PDGFRB being a high-degree hub within the HSC fibrogenic interaction network. Importantly, a previously published global HSC activation module failed to validate (JT p = 0.77); however, its core extracellular matrix and RUNX1\/2 sub-axis remained robust, whereas the widely claimed AP-1\/JUNB regulatory driver was not supported at the transcript level in the single-nucleus RNA-seq cohort data. These findings are consistent with an isolation-associated immediate-early gene response in enzymatically dissociated scRNA-seq data, given the flat-to-downward transcript-level trend in cryopreserved-tissue cohorts; transcript-level data cannot, however, exclude protein- or phosphorylation-level AP-1 activity. Targetable downstream components within the validated core architecture were annotated. By implementing per-donor verification, we successfully separated robust pathological features of MASH from platform-dependent artifacts. The validated SAMac program and the macrophage\u2013HSC PDGF axis, together with an associated RUNX subprogram, represent high-confidence, reproducibility-filtered candidate therapeutic nodes that require functional validation. These findings establish a reproducibility-first standard for single-cell translational research, and the validated programs are consistent with emerging models of inter-organ inflammatory circuitry in MASH.<\/jats:p>","DOI":"10.3390\/ijms27177920","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:12:25Z","timestamp":1788783145000},"page":"7920","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Conserved Macrophage-to-Hepatic Stellate Cell PDGF Axis in Human MASH Identified by Multi-Cohort sc\/snRNA-Seq Re-Analysis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0687-5778","authenticated-orcid":false,"given":"Hao","family":"Ling","sequence":"first","affiliation":[{"name":"Department of Surgery, Klinikum Rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Peiyu","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, NUTRIM\u2014Institute for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6229 HX Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Yanzhu","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Klinikum Rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1053\/j.gastro.2019.11.311","article-title":"Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis","volume":"158","author":"Schwabe","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ejim.2023.11.005","article-title":"Natural history of metabolic dysfunction-associated steatotic liver disease","volume":"122","author":"Lekakis","year":"2023","journal-title":"Eur. 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