{
  "abstract": "Background: Acute kidney injury (AKI) comprises heterogeneous proximal-tubule (PT) states in which regulated cell-death programs may emerge at different stages, complicating the interpretation of tissue markers and their translation to urine.\n\nMethods: Two independent human kidney transcriptomic cohorts were analyzed separately, and candidate genes were required to replicate in direction, adjusted significance, and an effect-size floor defined before candidate qualification. Candidates were localized in a patient-resolved single-nucleus kidney atlas using individual-level composition analysis and patient-state pseudobulk. Gene sets defined before correlation analysis assessed apoptosis, ferroptosis, pyroptotic inflammatory response, and programmed necrotic cell death. Urinary single-cell data examined cellular accessibility and composition, a longitudinal transplant-biopsy cohort constrained temporal interpretation, and ASPHD1 was silenced in commercial RPTEC/TERT1 cells exposed to cisplatin.\n\nResults: Nine genes met the strict cross-cohort replication criterion. ASPHD1 increased in native-kidney and transplant AKI and localized preferentially to the adaptive PT state. Apoptosis-associated transcriptional enrichment extended across adaptive and degenerative states, whereas ferroptosis-associated enrichment was most evident in degenerative PT. Candidate-to-death and death-to-immune correlations did not survive complete-family correction. ASPHD1 was detectable in urinary renal-proxy cells, but the unpaired urinary data and longitudinal transplant cohort did not establish diagnostic or recovery utility. In RPTEC/TERT1 cells, cisplatin induced ASPHD1, whereas ASPHD1-silencing reduced post-injury viability, increased annexin V-positive and cleaved-caspase-3-positive fractions, increased BAX and BBC3 while reducing BCL2, enhanced C11-BODIPY oxidation, reduced GPX4 fluorescence, and shifted SLC7A11, ACSL4, and PTGS2 in a ferroptosis-associated direction. z-VAD-FMK and ferrostatin-1 partially rescued the corresponding phenotypes.\n\nConclusion: Human AKI PTs show state-dependent enrichment of regulated cell-death-associated transcriptional programs. ASPHD1 is an adaptive-state candidate whose silencing increases apoptotic and ferroptosis-associated vulnerability in a commercial PT injury model.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Nephrology, Jinhua Hospital Affiliated to Zhejiang University, Jinhua, China",
    "Department of Nephrology, Rheumatology and Immunology, Chongqing University Affiliated Renji Hospital (The Fifth People’s Hospital of Chongqing), Chongqing, China",
    "Department of Emergency, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’an, Huai’an, China",
    "Department of Nephrology, The Affiliated Huai’an No. 1 People’s Hospital, Nanjing Medical University, Huai’an, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Zhengtong Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Qiaoqiao Gui"
    },
    {
      "affs": [
        0
      ],
      "name": "Hanjing Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaolei Lan"
    },
    {
      "affs": [
        2
      ],
      "name": "Yuan Liu"
    },
    {
      "affs": [
        3
      ],
      "name": "Yiyuan Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fgz8xhkhez01m.bib",
  "cited_by": 0,
  "doi": "10.3389/fcell.2026.1954743",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13736715/",
  "id": "fgz8xhkhez01m",
  "issns": [
    "2296-634X"
  ],
  "landing_url": "https://doi.org/10.3389/fcell.2026.1954743",
  "language": "en",
  "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": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2727|Acute Kidney Injury Research"
    ]
  ],
  "openalex": "W7223183201",
  "pdf_url": "https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2026.1954743/pdf",
  "pmcid": "PMC13736715",
  "pmid": "42991689",
  "published": "2026-10-22",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/fgz8xhkhez01m.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:22:06Z",
      "native_id": "PMC13736715",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fcell.2026.1954743"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2727|Acute Kidney Injury Research",
      "subfield": "general"
    }
  ],
  "title": "Regulated cell-death programs across patient-resolved proximal-tubule states in acute kidney injury: ASPHD1-silencing increases apoptosis and lipid peroxidation",
  "title_text": "Regulated cell-death programs across patient-resolved proximal-tubule states in acute kidney injury: ASPHD1-silencing increases apoptosis and lipid peroxidation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:06Z",
  "url": "https://research.draconitic.com/paper/fgz8xhkhez01m",
  "venue": "Frontiers in Cell and Developmental Biology",
  "versions": []
}