{
  "abstract": "Background: Diabetic retinopathy (DR) is a chronic diabetes-induced retinal microvascular complication that can lead to blindness. While vascular dysfunction and inflammation are recognized contributors, the regulatory mechanisms governing pyroptosis in DR remain poorly defined. Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2) has been implicated in calcium signaling and inflammatory responses, yet its role in DR pathogenesis is unclear. This study aimed to investigate whether ITPR2 regulates mitochondria-associated endoplasmic reticulum membrane formation, NLRP3 inflammasome activation, and microglial pyroptosis in DR.\n\nMethods: A diabetic rat model was established by intraperitoneal streptozotocin injection, and an advanced glycation end products (AGEs) -treated microglial cell model was used for in vitro studies. ITPR2 expression was manipulated by siRNA knockdown and plasmid overexpression. Mitochondrial morphology and function were assessed by transmission electron microscopy, MitoTracker staining, oxygen consumption rate, mitochondrial permeability transition pore opening, and membrane potential assays. Endoplasmic reticulum-mitochondria contacts were evaluated by imaging and Pearson correlation analysis. Pyroptosis was measured by flow cytometry, Western blotting of NLRP3, GSDMD-N, caspase-1, and IL-1β, and ELISA of inflammatory cytokines. Blood-retinal barrier integrity was examined by tight junction protein expression, FITC-dextran permeability, and transendothelial electrical resistance.\n\nResults: ITPR2 expression was elevated in diabetic rat retinas and AGEs stimulated microglia. ITPR2 knockdown suppressed AGEs induced mitochondria-associated endoplasmic reticulum membrane formation, reduced mitochondrial calcium overload, and ameliorated mitochondrial structural damage and dysfunction. These changes attenuated NLRP3 inflammasome activation and microglial pyroptosis, thereby reducing proinflammatory cytokine release. Consequently, endothelial tight junction protein degradation was alleviated and blood-retinal barrier permeability decreased. In vivo, intravitreal injection of adeno-associated virus shRNA targeting ITPR2 mitigated diabetes induced retinal capillary leakage, reduced acellular capillary formation, preserved tight junction protein expression, and suppressed microglial activation and pyroptosis in diabetic rats.\n\nConclusions: ITPR2 promotes DR progression by enhancing mitochondria-associated endoplasmic reticulum membrane formation, driving mitochondrial calcium overload and dysfunction, and activating NLRP3-mediated microglial pyroptosis, which ultimately disrupts the blood-retinal barrier. Targeting the ITPR2 signaling pathway may represent a promising therapeutic strategy for alleviating DR.\n\nGraphical Abstract:\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08785-9.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Ophthalmology, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, 210006 China",
    "Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, 215000 China",
    "School of Medicine, Nanjing University, Nanjing, 210006 China",
    "Department of Ophthalmology, Affiliated Wuxi Fifth Hospital of Jiangnan University, The Fifth People’s Hospital of Wuxi, Wuxi, 214000 China",
    "Department of Rheumatology and Immunology, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, 210006 China",
    "Graduate School of Dalian Medical University, Dalian Medical University, Dalian, 116000 China",
    "Department of Ophthalmology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, 210006 China",
    "Department of Ophthalmology, Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210006 China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Cong Liu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jinjin Xiang"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Suyu Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Chang He"
    },
    {
      "affs": [
        0
      ],
      "name": "Yinglin Liao"
    },
    {
      "affs": [
        0
      ],
      "name": "Rongpei Zhang"
    },
    {
      "affs": [
        3
      ],
      "name": "Ying Xia"
    },
    {
      "affs": [
        0
      ],
      "name": "Yueqin Chen"
    },
    {
      "affs": [
        4
      ],
      "name": "Genhong Yao"
    },
    {
      "affs": [
        0,
        5,
        6,
        7
      ],
      "name": "Zhenggao Xie"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/57j47wnmb9nzh.bib",
  "cited_by": 0,
  "doi": "10.1186/s12967-026-08785-9",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13737546/",
  "id": "57j47wnmb9nzh",
  "issns": [
    "1479-5876"
  ],
  "landing_url": "https://doi.org/10.1186/s12967-026-08785-9",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "1312|Inflammasome and immune disorders"
    ]
  ],
  "openalex": "W7201970431",
  "pdf_url": null,
  "pmcid": "PMC13737546",
  "pmid": "42989387",
  "published": "2026-08-08",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/57j47wnmb9nzh.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:22:42Z",
      "native_id": "PMC13737546",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s12967-026-08785-9"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Inflammasome and immune disorders",
      "subfield": "molecular-biology"
    }
  ],
  "title": "ITPR2 regulates microglial pyroptosis by Ca2+ transfer through mitochondria-ER contacts in Diabetic Retinopathy",
  "title_text": "ITPR2 regulates microglial pyroptosis by Ca2+ transfer through mitochondria-ER contacts in Diabetic Retinopathy",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:42Z",
  "url": "https://research.draconitic.com/paper/57j47wnmb9nzh",
  "venue": "Journal of Translational Medicine",
  "versions": []
}