Comput Biol Chem. 2026 Jul 29;125:109287. doi: 10.1016/j.compbiolchem.2026.109287. Online ahead of print.
ABSTRACT
BACKGROUND: Human heart failure involves multicellular transcriptional remodeling, but public transcriptomic studies often remain disconnected from cell-type localization and perturbational interpretation.
METHODS: We developed a reproducible computational workflow integrating human left-ventricular bulk transcriptomes, donor-level cell-type pseudobulk results from a human heart-failure single-cell/single-nucleus atlas, external snRNA-seq support, curated module scoring, focused ligand-receptor prioritization and LINCS/L1000 perturbational matching.
RESULTS: Cross-cohort analysis identified 14,358 same-direction HF-associated genes, including 1633 replicated HF-up and 785 replicated HF-down genes. Donor-level pseudobulk analysis localized disease remodeling to cardiomyocyte, fibroblast and myeloid compartments. Activated fibroblast and inflammatory myeloid programs defined a fibroinflammatory remodeling axis connected to context-dependent AKT-associated transcriptional shifts. External snRNA-seq support was strongest for fibroblast activation and AKT-associated remodeling, with etiology-dependent heterogeneity across validation resources. L1000FWD screening prioritized safety-aware perturbational hypotheses, including glimepiride and simvastatin as interpretable candidates requiring experimental validation.
CONCLUSIONS: This study provides a computational transcriptomic framework linking reproducible human HF signatures, cell-type-resolved fibroinflammatory remodeling and perturbational genomic prioritization without claiming drug efficacy or AKT causality.
PMID:42537336 | DOI:10.1016/j.compbiolchem.2026.109287