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Ubiquitin-Related Proteostatic Programs in Cycling Fibroblast-Lineage Remodeling After Myocardial Ischemic Injury: A Hypothesis Informed by Single-Cell and Spatial Transcriptomics

Year: 2026

Type: article

Abstract: Myocardial ischemia and reperfusion initiate spatially organized injury-repair programs that subsequently shape ventricular remodeling. Although cardiac fibroblasts are indispensable for scar formation, single-cell and spatial transcriptomic studies reveal temporally dynamic and regionally distinct fibroblast-lineage states. This critical narrative review integrates direct evidence from myocardial ischemia-reperfusion (I/R) with model-labeled evidence from permanent myocardial infarction, clinically heterogeneous human infarction, fibroblast-specific ubiquitin biology, cell-cycle regulation, and cardiac fibroblast atlases. A direct fibroblast I/R study identifies an HSP47-USP10-SMAD4 deubiquitination axis, whereas most other fibroblast ubiquitin-proteasome system (UPS) mechanisms derive from permanent infarction, non-ischemic cardiac stress, or in vitro systems. We propose that CCNB1-associated, G2/M-enriched cycling fibroblast-lineage states may impose heightened proteostatic demands within defined post-ischemic niches. The conceptual novelty is not that CCNB1 turnover or UPS activity is cardiac-specific; both are general features of proliferating cells. Rather, the framework asks whether fibroblast lineage, injury-model provenance, anatomical niche, temporal window, cell state, and substrate-specific UPS nodes jointly define proteostatic dependencies during post-ischemic remodeling. RNA-based ubiquitin-related signatures remain transcriptional proxies and do not directly quantify ubiquitinated substrates, ubiquitin-chain topology, enzyme activity, or proteasome flux. Resolving the proposed relationships will require spatial colocalization, protein-level and ubiquitin-remnant profiling, proteasome and ribosome assays, fibroblast-specific perturbation, and validation in human infarct tissue.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27146537