{
  "abstract": "Background: Mitochondrial dysfunction and dysregulated mitochondrial quality control (MQC) contribute to diabetes-associated myocardial injury. However, the potential involvement of proenkephalin (PENK) in cardiomyocyte injury and mitochondrial dysfunction under hyperglycemic conditions remains poorly understood. This study aimed to identify MQC-associated candidate genes and investigate the functional relevance of PENK in high-glucose-induced cardiomyocyte injury.\n\nMethods: GSE4745 was used as the discovery cohort for differential expression analysis, MQC-related pathway enrichment, and weighted gene co-expression network analysis (WGCNA). Candidate genes were prioritized using an integrated discovery-based scoring approach and further evaluated in three supportive GEO cohorts (GSE5606, GSE6880, and GSE197999). PENK expression and function were investigated in high-glucose-treated AC16 cardiomyocytes. Two independent PENK-targeting siRNAs were used to assess cell viability, apoptosis-associated protein expression, mitochondrial superoxide-related fluorescence, and mitochondrial membrane potential. MQC-associated protein expression was also examined by Western blotting.\n\nResults: Transcriptomic analysis identified 192 differentially expressed genes, including 58 MQC-related genes, and revealed alterations in fatty-acid oxidation, mitochondrial protein import, and mitophagy/autophagy-associated transcriptional programs. PENK emerged as a high-ranking candidate and exhibited increased expression in diabetic myocardial samples, with concordant expression changes across the supportive cohorts. High-glucose exposure increased PENK expression and impaired AC16 cell viability and mitochondrial function. PENK knockdown significantly improved cell viability, reduced cleaved caspase-3 expression and mitochondrial superoxide-related fluorescence, and increased the JC-1 red/green fluorescence ratio. These changes were accompanied by reduced PINK1, Parkin, and DRP1 protein abundance and increased MFN2 expression. Importantly, an independent si-PENK #2 experiment reproduced the improvements in cellular injury and mitochondrial phenotypes observed with si-PENK #1.\n\nConclusions: This study identifies PENK as an MQC-associated candidate involved in high-glucose-induced cardiomyocyte injury. Consistent findings from two independent PENK-targeting siRNAs indicate that PENK suppression attenuates cellular injury and improves mitochondrial functional phenotypes under hyperglycemic stress. These findings provide experimental evidence supporting the potential relevance of PENK to mitochondrial dysfunction in diabetes-associated myocardial injury.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Cardiac Surgery, Zhongshan Hospital Fudan University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Zheng Zuo"
    },
    {
      "affs": [
        0
      ],
      "name": "Beibei He"
    },
    {
      "affs": [
        0
      ],
      "name": "Yang Ming"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiaxing Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Kai Zhu"
    },
    {
      "affs": [
        0
      ],
      "name": "Hao Lai"
    },
    {
      "affs": [
        0
      ],
      "name": "Chunsheng Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jun Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Junyu Zhai"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0g4m242m7afc6.bib",
  "cited_by": 0,
  "doi": "10.3389/fcvm.2026.1970128",
  "fulltext_url": null,
  "id": "0g4m242m7afc6",
  "issns": [
    "2297-055X"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fcvm.2026.1970128/full",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-09",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/0g4m242m7afc6.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:23:33Z",
      "native_id": "10.3389/fcvm.2026.1970128",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fcvm.2026.1970128/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:2297-055X",
      "subfield": "cardiovascular"
    }
  ],
  "title": "Transcriptomic screening and in vitro validation suggest PENK involvement in mitochondrial quality-control dysregulation in diabetes-associated myocardial injury",
  "title_text": "Transcriptomic screening and in vitro validation suggest PENK involvement in mitochondrial quality-control dysregulation in diabetes-associated myocardial injury",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:23:33Z",
  "url": "https://research.draconitic.com/paper/0g4m242m7afc6",
  "venue": "Frontiers in Cardiovascular Medicine",
  "versions": []
}