Updates in acute graft‐versus‐host disease: From novel pathogenic mechanisms to emerging therapeutic targets

Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic haematopoietic stem cell transplantation (allo-HSCT), representing a leading cause of non-relapse mortality (NRM) and significant morbidity despite decades of intensive research. Its pathogenesis involves human leucocyte antigen (HLA) mismatch between donor and recipient and is initiated by conditioning-induced tissue damage that triggers alloreactive donor T-cell activation. Beyond classical immunological mechanisms, the intestinal microbiome and microbiome-derived metabolites have emerged as fundamental modulators of disease initiation and progression. Significant advances have been made in staging and risk stratification, with novel scoring systems integrating clinical parameters and biological biomarkers to more accurately predict treatment response and overall outcome. In the treatment of aGVHD, the last decade has witnessed considerable progress, most notably the approval of ruxolitinib, which has fundamentally changed the management landscape of steroid-refractory aGVHD (SR-aGVHD). Intestinal aGVHD, which carries the highest mortality among disease manifestations, remains a particularly challenging entity. Notably, the enteroendocrine system has recently gained attention as a pathogenic contributor, with early-phase trials exploring the therapeutic potential of exogenous hormone administration. In this review, we discuss both well-established and emerging evidence on the pathogenesis, staging and risk stratification and treatment of aGVHD, with particular focus on novel therapeutic strategies.