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<p>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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月27日

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  • Shihan Xu,
  • Chunxiao Ju,
  • Mengmeng Zhu,
  • Yajie Cai,
  • Fengqin Xu,
  • Yanfei Liu,
  • Yue Liu

摘要

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.