2. Academic Validation
  3. SPHK1 deficiency promotes intestinal homeostasis by ameliorating ER stress-induced gastrointestinal injury during murine graft-versus-host disease

SPHK1 deficiency promotes intestinal homeostasis by ameliorating ER stress-induced gastrointestinal injury during murine graft-versus-host disease

  • Sci China Life Sci. 2026 May;69(5):1634-1649. doi: 10.1007/s11427-025-3144-0.
Di Wu # 1,  Xinhui Zhao # 1,  Yajing Pu # 1,  Qianwen Lu 1,  Jiulei Shui 1,  Yichu Chen 2 3,  Kang Yang 1,  Bangyi Yang 1,  Gaoxiang Li 1,  Hong Zhou 4 5,  Meng Zhou 6 7
Affiliations

Affiliations

  • 1 School of Life Sciences, Anhui Medical University, Hefei, 230032, China.
  • 2 Clinical Pathology Center, The First Affiliated Hospital of Anhui Medical University, Hefei, 230012, China.
  • 3 Clinical Pathology Center, Anhui Public Health Clinical Center, Hefei, 230012, China.
  • 4 School of Life Sciences, Anhui Medical University, Hefei, 230032, China. [email protected].
  • 5 School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China. [email protected].
  • 6 School of Life Sciences, Anhui Medical University, Hefei, 230032, China. [email protected].
  • 7 Department of Hematology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230061, China. [email protected].
  • # Contributed equally.
PMID: 41627669 DOI: 10.1007/s11427-025-3144-0
Abstract

Graft-versus-host disease (GVHD) remains a major challenge in successful allogeneic hematopoietic stem cell transplantation. Here, we report that inhibiting sphingosine kinase 1 (SphK1), an enzyme that phosphorylates sphingosine to bioactive sphingosine-1-phosphate (S1P), effectively ameliorates acute GVHD (aGVHD) without compromising the graft-versus-leukemia effect. The absence of SphK1 in the host exerts a beneficial effect on maintaining gut homeostasis by limiting intestinal epithelial cell (IEC) and intestinal stem cell (ISC) injury. This reduces gut permeability and prevents Bacterial translocation, decreasing MHC II levels in IECs and donor T-cell infiltration. Persistent endoplasmic reticulum (ER) stress is observed during GVHD in the gastrointestinal tract and contributes to IEC injury. SphK1 deficiency attenuates IEC damage by alleviating ER stress, which can be reversed by supplementation with exogenous S1P. FTY720, an S1P receptor antagonist, significantly inhibits ER stress-induced IEC injury. Our findings highlight the pathogenic role of host SphK1 in gastrointestinal injury during aGVHD and suggest that targeting SphK1 could be a therapeutic strategy for managing this condition.

Keywords

ER stress; SPHK1; bacterial translocation; graft-versus-host disease.

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