ArticleInternational journal of molecular sciences2026
Explainable Artificial Intelligence and Gene-Network Analysis Prioritise a TREM2/LGALS3/GPNMB Scar-Associated Macrophage Programme in Human Liver Cirrhosis.
Article in International journal of molecular sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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- 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-receptor 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 0.61-0.65. 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.
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