ArticleHuman mutation2026
S100A8/S100A9 Links Diabetic Stress to Cardiac Progenitor Cell Dysfunction and Fibrotic Heart Failure: An Integrated Transcriptomic, Single-Cell, and Functional Study.
Article in Human mutation, 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
Background: Diabetes markedly increases the risk of heart failure, yet the molecular signals connecting metabolic stress, myocardial fibrosis, and impaired cardiac repair remain incompletely understood. Methods: We integrated bulk transcriptomic data from postischemic hearts (GSE26887), fibrosis-related genes from the CTD database, protein-protein interaction (PPI) analysis, and pathway enrichment (GO, KEGG, GSEA, and GSVA) to identify candidate mediators in diabetic versus nondiabetic heart failure. Single-cell RNA-sequencing datasets were analyzed with Seurat to map the cellular distribution of key genes. Pan-cancer analyses using TCGA cohorts were performed to evaluate prognostic, immune, and tumor mutation burden (TMB) correlations. Mechanistic validation was conducted in human cardiac progenitor cells (CPCs) exposed to normoglycemia or high glucose with S100A9 knockdown or overexpression, recombinant S100A8/A9, and a neutralizing S100A9 antibody. Cell viability (CCK-8); qPCR panels for fibrosis, inflammation, and metabolic genes; ROS production (DCF-DA and MitoSOX); and mitochondrial respiration were quantified. Results: Differential expression and PPI network analyses identified S100A8 as a fibrosis-related hub specifically enriched in diabetic heart failure. Single-cell mapping revealed predominant S100A8 expression in CPCs rather than mature cardiomyocytes. Pathway analyses linked S100A8 to collagen fibril organization, ECM-receptor interaction, oxidative phosphorylation, and fatty acid Conclusions: S100A8/S100A9 emerges as a central mediator linking hyperglycemia-induced oxidative stress, metabolic inflexibility, and fibrotic reprogramming of CPCs, thereby promoting diabetic heart failure. S100A8/S100A9 may serve as a biomarker and therapeutic target at the interface of immunometabolism, cardiac regeneration, and cardio-oncology.
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