{
  "abstract": "Background: Clear cell renal cell carcinoma (ccRCC), the predominant histological subtype of kidney malignancies, is characterized by metabolic dysregulation and therapeutic resistance. Although the intracellular antioxidant paraoxonase 2 (PON2) is frequently dysregulated across multiple cancers, its biological role in ccRCC-particularly the contribution of its enzymatic activity and interplay with the tumor immune microenvironment-remains poorly defined. Methods: Multi-cohort analysis integrating TCGA, ICGC, GEO, and CPTAC datasets was combined with single-cell transcriptomic profiling, survival and Cox regression modeling, immune infiltration estimation, and in vitro loss- and gain-of-function experiments in ccRCC cell lines. Results: PON2 was markedly elevated in ccRCC tissues, predominantly localizing to malignant epithelial and endothelial cells as determined by single-cell transcriptomic profiling. High PON2 expression correlated with advanced T/M stages and independently predicted poor prognosis. Functional experiments showed that PON2 silencing was associated with reduced tumor cell proliferation, invasion, and glycolysis, while rescue experiments using wild-type-but not S311C mutant-PON2 partially restored these phenotypes. PON2 expression was associated with glycolysis-related metabolic changes and CEBPB-related expression of downstream glycolytic targets, including LDHA and PGK1. Furthermore, PON2-high tumors showed transcriptomic features consistent with an immunosuppressive microenvironment, with higher computational estimates of CD8⁺ T-cell infiltration accompanied by elevated immune checkpoint expression (PD-L1, CTLA4) and higher estimated abundance of immunosuppressive populations (Tregs, MDSCs). Conclusions: Collectively, our findings identify PON2 as a candidate biomarker associated with ccRCC progression and CEBPB-related glycolysis and features consistent with an immunosuppressive microenvironment.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Urology & Urology Laboratory, The Third Affiliated Hospital of Nanjing Medical University, 68 Gehu Middle Road, Wujin District, Changzhou 213003, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Zhiyu Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Wei Yun"
    },
    {
      "affs": [
        0
      ],
      "name": "Ting Hong"
    },
    {
      "affs": [
        0
      ],
      "name": "Chuan Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Guangming He"
    },
    {
      "affs": [
        0
      ],
      "name": "Shenglin Gao"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaokai Shi",
      "orcid": "0000-0002-2975-2658"
    },
    {
      "affs": [
        0
      ],
      "name": "Li Zuo"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cyd6smaexeq0p.bib",
  "cited_by": 0,
  "doi": "10.3390/cancers18193086",
  "fulltext_url": "https://europepmc.org/articles/PMC13664073",
  "id": "cyd6smaexeq0p",
  "issns": [
    "2072-6694"
  ],
  "landing_url": "https://europepmc.org/article/MED/42882781",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1308|Paraoxonase enzyme and polymorphisms"
    ]
  ],
  "openalex": "W7214087414",
  "pdf_url": "https://europepmc.org/articles/PMC13664073?pdf=render",
  "pmcid": "PMC13664073",
  "pmid": "42882781",
  "published": "2026-09-23",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cyd6smaexeq0p.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:16Z",
      "native_id": "MED:42882781",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42882781"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:2072-6694",
      "subfield": "oncology"
    }
  ],
  "title": "Association of PON2 and Its S311C Substitution with Tumor Progression and Its Significance as an Immune-Associated Prognostic Indicator in Clear Cell Renal Cell Carcinoma.",
  "title_text": "Association of PON2 and Its S311C Substitution with Tumor Progression and Its Significance as an Immune-Associated Prognostic Indicator in Clear Cell Renal Cell Carcinoma.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:16Z",
  "url": "https://research.draconitic.com/paper/cyd6smaexeq0p",
  "venue": "Cancers",
  "versions": []
}