[Inflammatory memory in intestinal stem cells: reframing GVHD pathogenesis]

We and others have demonstrated that epithelial stem cells are primary targets in acute graft-versus-host disease (GVHD) across multiple target organs, including the skin, liver, and gastrointestinal tract, thereby impairing tissue homeostasis and resilience. While previous studies have demonstrated the quantitative loss of epithelial stem cells, the qualitative changes that drive stem cell dysfunction remain poorly defined. Recent studies have revealed that epigenetically imprinted "inflammatory memory" in intestinal stem cells during acute GVHD leads to impaired epithelial regenerative capacity and enhanced inflammatory responses to subsequent inflammatory environments. Collectively, these findings suggest that inflammatory memory in intestinal stem cells contributes to GVHD pathogenesis and to GVHD flares after successful treatment. Furthermore, inflammatory memory in tissue stem cells represents a promising novel therapeutic target for GVHD beyond conventional immunosuppression. In this review, we introduce this emerging concept of inflammatory memory, revisit GVHD pathogenesis from the perspective of inflammatory memory in intestinal stem cells, and discuss the underlying molecular mechanisms and clinical implications.