Work

snRNA-seq identifies Fmo2+ fibroblasts as drivers of hyperglycemic memory-induced cardiac injury

Year: 2026

Type: article

Abstract: Despite intensive glycemic control, diabetic cardiomyopathy (DCM) often progresses due to hyperglycemic memory (HGM), yet the specific cardiac cells perpetuating this injury remain unknown. To address this, we performed single-nucleus RNA sequencing (snRNA-seq) on hearts from an HGM rat model. Our analysis of 86,120 nuclei revealed HGM-specific inflammatory and epigenetic reprogramming signatures. Fibroblasts emerged as potential mediators, appearing to drive extracellular matrix remodeling via upregulated LAMININ and COLLAGEN signaling. We uncovered a distinct HGM-specific fibroblast subpopulation characterized by oxidative stress and H3K27 demethylation. Integrative analysis prioritized Fmo2 as a key pathogenic candidate, which was further supported via Mendelian randomization and clinical data as a putative causal gene. This study suggests that a pathogenic Fmo2 + fibroblast subpopulation may act as a pathological “memory carrier,” providing novel mechanistic insights and proposing exploratory therapeutic avenues for HGM-induced cardiac damage beyond glycemic control.

Source: npj Metabolic Health and Disease

DOI: 10.1038/s44324-026-00113-5