Stabilization of HIF-1α using the prolyl hydroxylase inhibitor roxadustat reduces gastrointestinal graft-versus-host disease

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for high-risk hematologic malignancies, yet its efficacy is limited by the onset of graft-versus-host disease (GVHD). Acute GVHD (aGVHD) primarily affects epithelial cells of the gastrointestinal tract, skin, and liver by the involvement of alloreactive T-cells and pro-inflammatory cytokines. The barrier-protective role of hypoxia-inducible factor (HIF), regulated by prolyl hydroxylase, has been significantly implicated in hypoxic inflammatory conditions. In this study, Roxadustat, a prolyl hydroxylase inhibitor, was tested in a murine model of aGVHD (C57BL/6J → BALB/cJ) to decrease hypoxia-mediated early gastrointestinal injury. Recipients were treated with roxadustat or vehicle intraperitoneally daily for the first week post-transplant, and then twice a week till day 42. Roxadustat significantly improves survival by day + 42 with reduced clinical GVHD symptoms. Reduced gut pathology with significant reduction of serum IFN- γ and TNF-α levels, suggesting a decreased systemic inflammation. Roxadustat significantly decreased T-cell infiltration and prevented TNF-α-induced intestinal epithelial cell apoptosis through HIF-1α-dependent repression of Fas-associated death domain protein (FADD) and cleaved caspase 3. In vitro, roxadustat suppressed TNF-α production by peritoneal macrophages and mixed lymphocyte reaction. These results suggest that roxadustat attenuates early gut injury, offering an alternative strategy for acute GVHD following allo-HSCT.