Targeting IRE1α/XBP1 signaling synergizes with cyclosporine A to ameliorate skin allograft rejection
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.
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BibTeX
@article{longhui2026targeting,
title = {{Targeting IRE1α/XBP1 signaling synergizes with cyclosporine A to ameliorate skin allograft rejection}},
author = {Zeng Longhui and Chen Guidong and Xu Peikang and Li Guanghui and Zhang Peng and Liu WenJia and Chen Zheng and Ning Fen and Lai Xingqiang},
journal = {Scientific Reports},
year = {2026},
month = sep,
doi = {10.1038/s41598-026-73090-w},
url = {https://www.nature.com/articles/s41598-026-73090-w},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting IRE1α/XBP1 signaling synergizes with cyclosporine A to ameliorate skin allograft rejection
AU - Zeng Longhui
AU - Chen Guidong
AU - Xu Peikang
AU - Li Guanghui
AU - Zhang Peng
AU - Liu WenJia
AU - Chen Zheng
AU - Ning Fen
AU - Lai Xingqiang
PY - 2026
DA - 2026/09/30
JO - Scientific Reports
DO - 10.1038/s41598-026-73090-w
UR - https://www.nature.com/articles/s41598-026-73090-w
AB - 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.
SN - 2045-2322
ER -