Editor's Note: Steroid-refractory acute graft-versus-host disease (SR-aGVHD) remains one of the greatest clinical challenges following allogeneic hematopoietic stem cell transplantation (allo-HSCT). At the 2026 European Hematology Association (EHA) Congress, Professor Song Qingxiao from the Second Affiliated Hospital of Army Medical University presented an oral presentation reporting his team's latest discoveries on the pathogenesis of SR-aGVHD. The study demonstrated that 7-ketocholesterol (7-KC) can restore steroid sensitivity by reshaping T-cell lineage metabolism, providing a novel strategy for pre-transplant risk stratification and individualized intervention. During the meeting, Hematology Frontier interviewed Professor Song to discuss the clinical significance of these findings and their potential to overcome one of the most difficult barriers in SR-aGVHD management. Hematology Frontier: Steroid-refractory acute GVHD remains one of the most challenging complications after allogeneic transplantation. Your study is the first to demonstrate a close association between 7-ketocholesterol deficiency and steroid resistance. How does this discovery reshape our understanding of the mechanisms underlying SR-aGVHD? Does it suggest that metabolic dysregulation plays a much more important role than previously recognized?
Professor Song Qingxiao:
It was a great honor to present our latest research on the mechanisms underlying steroid-refractory acute graft-versus-host disease (SR-aGVHD) at this year’s EHA Congress.
Our study offers four major advances.
First, we are the first to elucidate the mechanism of T-cell steroid resistance from the perspective of cellular metabolism. SR-aGVHD has long been one of the most difficult complications in allogeneic hematopoietic stem cell transplantation. Previous studies have primarily focused on inflammatory cytokines, signaling pathways, and immune cell imbalance, while very few have investigated the intrinsic metabolic mechanisms of T cells. To address the longstanding clinical observation that patients receiving identical conditioning regimens and glucocorticoid doses often exhibit markedly different treatment responses, we explored metabolic pathways and identified 7-ketocholesterol as a key metabolite capable of distinguishing steroid-sensitive from steroid-resistant T cells. More importantly, both in vitro and in vivo functional experiments demonstrated that 7-ketocholesterol is not merely a biomarker but also a functional metabolite capable of reversing steroid resistance in T cells.
Second, our study uncovers a previously unrecognized role of 7-ketocholesterol in transplantation immune tolerance. Traditionally, 7-ketocholesterol has been regarded as a harmful metabolite associated with atherosclerosis and oxidative stress. Our findings demonstrate that, within the specific context of SR-aGVHD, 7-ketocholesterol exerts beneficial immunomodulatory effects, fundamentally changing our understanding of its biological function.
Third, we innovatively identified biomarkers by examining the metabolic status of donor T cells. Previous biomarker studies in acute GVHD have largely focused on post-transplant recipient serum markers or immune cell subsets. Our study is the first to demonstrate that the metabolic profile of donor T cells within the graft itself can predict their subsequent responsiveness to glucocorticoid therapy after transplantation.
Finally, we demonstrated that steroid resistance is reversible, highlighting substantial translational potential. Our findings show that steroid resistance is not an irreversible terminal state but can be corrected through metabolic intervention. If successfully translated into clinical practice, pre-transplant metabolic profiling of donor T cells could enable early intervention and personalized treatment planning before transplantation, rather than relying on salvage therapy after steroid resistance has already developed.
Hematology Frontier: Your study shows that 7-ketocholesterol enhances glucocorticoid receptor activity and promotes the conversion of Th17 cells into regulatory T cells (Tregs), thereby restoring steroid sensitivity. Mechanistically, how does 7-KC bridge metabolic regulation, epigenetic remodeling, and immune reprogramming?
Professor Song Qingxiao:
In simple terms, 7-ketocholesterol serves as a critical bridge connecting cellular metabolism, epigenetic regulation, and T-cell lineage remodeling.
First, it is not only an intrinsic metabolic product of T cells but also a central regulator of T-cell function. Metabolic changes have traditionally been viewed merely as consequences of T-cell activation. Our study demonstrates that 7-ketocholesterol actively regulates T-cell biology. It suppresses the proliferation of steroid-resistant T cells while, more importantly, driving lineage conversion from pro-inflammatory Th17 cells toward immunosuppressive regulatory T cells (Tregs). This lineage reprogramming represents the central mechanism underlying the reversal of steroid-resistant aGVHD observed in our study.
Second, this phenotypic conversion is driven by extensive epigenetic remodeling. Under the influence of 7-ketocholesterol, the epigenetic program of T cells is comprehensively reshaped, promoting stable differentiation toward the Treg phenotype.
Third, these epigenetic alterations ultimately translate into functional changes in cellular identity. Our in vitro experiments demonstrated that 7-ketocholesterol consistently promotes Th17-to-Treg transdifferentiation under both Th17- and Treg-polarizing conditions while maintaining stable Treg expansion.
Finally, our in vivo mouse model confirmed the therapeutic potential of this metabolic intervention. In steroid-refractory aGVHD mice, combining 7-ketocholesterol with glucocorticoids significantly reduced disease severity, protected target organs from injury, and markedly prolonged survival.
Taken together, 7-ketocholesterol is far more than a metabolic biomarker. It represents a functional therapeutic molecule capable of reversing steroid-refractory aGVHD by directing T-cell fate decisions.
Hematology Frontier: Your findings suggest that 7-KC may serve not only as a biomarker for predicting glucocorticoid responsiveness but also as a novel therapeutic target. Based on your current results, what are the key challenges that remain before clinical translation can be achieved? Are there plans for future clinical studies?
Professor Song Qingxiao:
Ultimately, translating our basic research into clinical practice is the primary goal of this work. Steroid-refractory acute GVHD remains a major unmet clinical need, and our research has followed the classic translational medicine pathway: identifying a clinical problem, investigating its underlying mechanisms in the laboratory, and ultimately developing clinically applicable solutions.
Regarding biomarker development, our single-center clinical dataset was still incomplete when we submitted our EHA abstract. However, shortly before traveling to Stockholm, we obtained updated clinical data with highly encouraging results, which I also presented during my oral presentation.
Our study confirmed that lower levels of 7-ketocholesterol in donor graft T cells are associated with a significantly higher risk of developing steroid-refractory acute GVHD after transplantation. These findings further support the potential of 7-ketocholesterol as a predictive biomarker. We also observed possible associations with organ-specific acute GVHD, which we plan to validate in larger multicenter studies.
From the perspective of clinical translation, our next objective is to determine whether targeting the 7-ketocholesterol metabolic pathway can provide therapeutic benefit. At present, additional studies are needed to establish the biological safety profile and pharmacokinetics of 7-ketocholesterol. Beyond the molecule itself, other metabolites within the same pathway, structural analogs, and combination strategies with existing second-line therapies for steroid-refractory acute GVHD all represent promising future research directions.
If these questions can be addressed successfully, we may ultimately be able to predict the risk of steroid-refractory GVHD before transplantation, implement early intervention, perform individualized risk stratification, and achieve truly precise management of GVHD. That has always been the vision driving our translational research.
Expert Profile
Professor Song Qingxiao
Second Affiliated Hospital, Army Medical University (PLA)
Professor Song Qingxiao is a Distinguished Professor, Principal Investigator, and Master’s Supervisor at the Second Affiliated Hospital of Army Medical University.
He is a recipient of the inaugural New Chongqing Overseas Talent Program, Secretary of the Transplantation and Immunotherapy Group of the Chinese Society of Hematophysiology, a member of the Expert Committee on Aging Intervention and Chronic Disease Prevention of the China Health Promotion Foundation, and a member of the American Society of Hematology (ASH).
From 2014 to 2022, he completed doctoral training, postdoctoral research, and served as a Staff Scientist at City of Hope National Medical Center in the United States. His research focuses on immune tolerance following hematopoietic stem cell transplantation, the cellular and molecular mechanisms underlying graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects, and the translational development of targeted therapies. As first or corresponding author, he has published numerous high-impact studies in journals including Blood, Nature Communications, Journal of Clinical Investigation, and JCI Insight. He has received funding from the National Natural Science Foundation of China and the Chongqing Natural Science Foundation and served as the lead author of the Chinese Expert Consensus on the Diagnosis and Treatment of Chronic Graft-versus-Host Disease.
