{
  "abstract": "Sepsis is characterized by profound immune dysregulation and metabolic remodeling, yet how hypoxia shapes macrophage-state diversity remains incompletely defined. Here, we integrated single-cell transcriptomic profiles from early- and late-stage sepsis with healthy controls to construct a hypoxia-centered immune atlas. The single-cell landscape identified 103,851 cells across 23 clusters, while hypoxia scoring showed that macrophages displayed the strongest hypoxic activity, particularly in early sepsis. Macrophages were further stratified into low-, intermediate- and high-hypoxic states, revealing a continuous transcriptional gradient rather than discrete subsets. High-hypoxic macrophages exhibited increased CytoTRACE-defined plasticity, occupied intermediate-to-late pseudotime states, and showed enhanced inflammatory and metabolic pathway activation. Cell–cell communication analysis positioned these macrophages as bidirectional signaling hubs, with amplified MIF, CCL, ANNEXIN and IL1-related interactions. Integrated high dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA) and machine-learning analyses identified hypoxia-associated hub genes, among which TIPARP emerged as a key regulator linked to macrophage hypoxic remodeling. TIPARP was preferentially enriched in high-hypoxic macrophages and experimentally validated as responsive to hypoxia and inflammatory stimulation, with knockdown can enhance HIF1A and VEGF induction. Drug-sensitivity prediction further suggested state-specific vulnerabilities of hypoxia-adapted macrophages. Together, these findings define hypoxia as a central determinant of macrophage heterogeneity in sepsis and nominate TIPARP as a candidate target for immunometabolic intervention.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University",
    "Department of Neurosurgery, The Affiliated Hospital of Qingdao University",
    "Dapartment of Pathology, The Affiliated Hospital of Qingdao University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yanfei Yu"
    },
    {
      "affs": [
        1
      ],
      "name": "Zhixing Wang"
    },
    {
      "affs": [
        2
      ],
      "name": "Yongxing Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Cai Jing"
    },
    {
      "affs": [
        0
      ],
      "name": "Xia Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2mnyb91vv0xe7.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1941002",
  "fulltext_url": null,
  "id": "2mnyb91vv0xe7",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1941002/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",
      "2713|Sepsis Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7224013270",
  "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1941002/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-27",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/2mnyb91vv0xe7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:17Z",
      "native_id": "10.3389/fimmu.2026.1941002",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1941002/full"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2713|Sepsis Diagnosis and Treatment",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "Hypoxia-driven macrophage heterogeneity in sepsis: single-cell transcriptomic insights into immune reprogramming and therapeutic targeting",
  "title_text": "Hypoxia-driven macrophage heterogeneity in sepsis: single-cell transcriptomic insights into immune reprogramming and therapeutic targeting",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:17Z",
  "url": "https://research.draconitic.com/paper/2mnyb91vv0xe7",
  "venue": "Frontiers in Immunology",
  "versions": []
}