{
  "abstract": "This study investigated the synergistic effect and immunomodulatory mechanism of combining IRE1α/XBP1 pathway inhibition with cyclosporine A (CsA) against acute rejection in a murine allogeneic skin transplant model. BALB/c-to-C57BL/6 skin allograft recipients were treated with the IRE1α/XBP1 inhibitor 4µ8C, alone or combined with perioperative short-term CsA. Graft survival and histopathology were monitored. Flow cytometry was employed to analyze immune cells in lymphoid organs and to measure serum donor-specific antibodies (DSA). Intragraft mRNA expression was quantified by RT-qPCR and serum cytokine levels were determined using multiplex immunoassays. Pharmacological IRE1α/XBP1 inhibition downregulated endoplasmic reticulum stress-related genes in allografts, delayed rejection, and reduced systemic inflammation. The combination therapy (4µ8C + CsA) further prolonged allograft survival and reduced inflammatory infiltration. Mechanistically, the combined treatment achieved its dual immunomodulatory effect by reducing the frequency of CD8⁺ T cells and suppressing the generation of effector memory T cells and follicular helper T cells, while promoting the expansion of regulatory T cells (as evidenced by increased CD4⁺Foxp3⁺ Treg frequencies among CD3⁺ T cells). It also suppressed DSA production and intragraft pro-inflammatory cytokine expression. Inhibition of the IRE1α/XBP1 pathway synergizes with CsA to enhance efficacy through coordinated regulation of T-cell differentiation and mitigation of inflammatory responses. This presents a novel combinatorial strategy that has the potential to improve transplant outcomes.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "Zeng Longhui"
    },
    {
      "name": "Chen Guidong"
    },
    {
      "name": "Xu Peikang"
    },
    {
      "name": "Li Guanghui"
    },
    {
      "name": "Zhang Peng"
    },
    {
      "name": "Liu WenJia"
    },
    {
      "name": "Chen Zheng"
    },
    {
      "name": "Ning Fen"
    },
    {
      "name": "Lai Xingqiang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e89znxpgatjcq.bib",
  "cited_by": 0,
  "doi": "10.1038/s41598-026-73090-w",
  "fulltext_url": null,
  "id": "e89znxpgatjcq",
  "issns": [
    "2045-2322"
  ],
  "landing_url": "https://www.nature.com/articles/s41598-026-73090-w",
  "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",
      "2747|Organ and Tissue Transplantation Research"
    ]
  ],
  "openalex": "W7214732559",
  "pdf_url": "https://www.nature.com/articles/s41598-026-73090-w_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-30",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/e89znxpgatjcq.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:19Z",
      "native_id": "10.1038/s41598-026-73090-w",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41598-026-73090-w"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2747|Organ and Tissue Transplantation Research",
      "subfield": "surgery"
    }
  ],
  "title": "Targeting IRE1α/XBP1 signaling synergizes with cyclosporine A to ameliorate skin allograft rejection",
  "title_text": "Targeting IRE1α/XBP1 signaling synergizes with cyclosporine A to ameliorate skin allograft rejection",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:19Z",
  "url": "https://research.draconitic.com/paper/e89znxpgatjcq",
  "venue": "Scientific Reports",
  "versions": []
}