Decitabine Protects Against Autoimmunity‐Mediated Bone Loss and Death in Foxp3‐Deficient Scurfy Mice

ABSTRACT Foxp3‐dependent regulatory T cells (Tregs) are essential for immune tolerance and skeletal homeostasis. Loss of Foxp3 function results in severe immune dysregulation, enteropathy and osteopenia, as observed in human IPEX syndrome and the scurfy (SF) mouse model. This study evaluated the therapeutic potential of the DNA methyltransferase inhibitor decitabine (DAC) to mitigate immune pathology and skeletal deterioration in Foxp3‐deficient SF mice. SF mice received DAC treatment for 12 weeks and were monitored for survival, body weight and splenomegaly. Bone microarchitecture was assessed using microcomputed tomography. Serum bone turnover markers, immune cell subsets, inflammatory cytokines, gene expression profiles, haematopoietic progenitors and osteoclastogenesis in T cell–macrophage co‐cultures were analysed to determine DAC's systemic and skeletal effects. DAC treatment significantly prolonged survival, stabilized body weight and reduced splenomegaly in SF mice. Trabecular bone mass was preserved, accompanied by reduced serum CTX levels, indicating suppression of osteoclast‐mediated bone resorption. DAC attenuated systemic inflammation by decreasing pathogenic TCRβ + T cells, Th17 cells, IL‐17A + T cells and autoantibody‐producing B‐cell subsets in spleen and bone marrow. Expression of osteoclastogenic cytokines (TNF‐α, RANKL and IL‐6) and inflammatory genes was normalized. DAC also corrected haematopoietic progenitor abnormalities and reduced osteoclast formation in co‐culture assays. These findings demonstrate that DAC restores immune balance, suppresses excessive osteoclastogenesis, preserves skeletal integrity, and improves survival in Foxp3‐deficient SF mice. The results support DAC's translational potential as a therapeutic strategy for IPEX syndrome and related disorders characterized by Treg dysfunction.