{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:07:31Z","timestamp":1789103251795,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Plan","award":["2022YFE0210600"],"award-info":[{"award-number":["2022YFE0210600"]}]},{"name":"National Key Research and Development Plan","award":["2019YFA0111300"],"award-info":[{"award-number":["2019YFA0111300"]}]},{"name":"Guangdong Province Grant for Belt and Road Joint Laboratory","award":["2022B1212050004"],"award-info":[{"award-number":["2022B1212050004"]}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2021A1515220095"],"award-info":[{"award-number":["2021A1515220095"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Guangzhou Science and technology plan project","award":["2023B01J1004"],"award-info":[{"award-number":["2023B01J1004"]}]},{"name":"Guangzhou Science and technology plan project","award":["2023A03J0253"],"award-info":[{"award-number":["2023A03J0253"]}]},{"name":"Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences","award":["GIBHBRP23-01"],"award-info":[{"award-number":["GIBHBRP23-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Macrophages organise the fibrotic niche of liver cirrhosis. The scar-associated macrophage state is well described, but the genes that define it have rarely been ranked in an unbiased, model-based way, and the statistical limits of such re-analyses are seldom reported. Here we set out to re-derive the scar-associated macrophage programme without supervision, to rank its constituent genes by convergent computational evidence, and to state explicitly what a cohort of this size can and cannot support. We re-analysed 58,358 single-cell transcriptomes from five uninjured and five cirrhotic human livers (GEO GSE136103; Edinburgh DataShare DS_10283_3433). After quality control, Harmony batch integration and Leiden clustering, the mononuclear-phagocyte compartment (9869 cells) was re-clustered. We applied donor-level compositional testing stratified within the CD45+\/CD45\u2212 sorted fractions, donor-level pseudobulk differential expression, three classifiers with SHapley Additive exPlanations (SHAP) under donor-grouped cross-validation, transcription-factor differential expression, diffusion pseudotime, ligand\u2013receptor modelling and CellOracle in silico perturbation. The donor, never the cell, was the unit of analysis for every condition comparison. A discrete macrophage cluster (390 cells; 60.5% cirrhotic; contributed by all 10 donors) carried a coherent lipid\/scar programme comprising LGALS3, GPNMB, TREM2, CD9, FABP5, APOE, APOC1 and CTSD, and was recovered in all 22 clustering configurations tested. The integrated prioritisation was robust: seven genes remained in the top 20 in 100% of 1000 Dirichlet re-weightings. MAFB, MITF and TFEC were significantly enriched transcription factors, and pseudotime placed the state downstream of a monocyte root. Three findings temper these results. No lineage showed a significant compositional change after multiple-testing correction, and every test was underpowered for its observed effect. No gene reached significance in donor-level pseudobulk differential expression. Classifier performance of 0.99 reflects the circularity of predicting a cluster defined from the same matrix; the non-circular contrast of cirrhotic versus uninjured cells gave 0.61\u20130.65. Overall, a documented, fully reproducible framework re-derives and ranks a TREM2\/LGALS3\/GPNMB scar-associated macrophage programme and nominates galectin-3, GPNMB and the SPP1 axis as prioritised, clinically unproven candidates. The prioritisation is a hypothesis requiring independent, spatial, protein-level and functional validation.<\/jats:p>","DOI":"10.3390\/ijms27188023","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T12:26:11Z","timestamp":1788956771000},"page":"8023","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Explainable Artificial Intelligence and Gene-Network Analysis Prioritise a TREM2\/LGALS3\/GPNMB Scar-Associated Macrophage Programme in Human Liver Cirrhosis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5474-2622","authenticated-orcid":false,"given":"Shah","family":"Faisal","sequence":"first","affiliation":[{"name":"Center for Cell Lineage Technology and Engineering, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangzhou 510530, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1673-1272","authenticated-orcid":false,"given":"Muhammad Adeel","family":"Ejaz","sequence":"additional","affiliation":[{"name":"Center for Cell Lineage Technology and Engineering, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Piniel Alphayo","family":"Kambey","sequence":"additional","affiliation":[{"name":"Center for Cell Lineage Technology and Engineering, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China"},{"name":"China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangzhou 510530, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5637-1241","authenticated-orcid":false,"given":"Abdul","family":"Malik","sequence":"additional","affiliation":[{"name":"Center for Cell Lineage Technology and Engineering, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangzhou 510530, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Yin-Xiong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Cell Lineage Technology and Engineering, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangzhou 510530, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.jhep.2023.03.017","article-title":"Global burden of liver disease: 2023 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