ArticleHaematologica2026
KLF4 overexpression protects against complementmediated endothelial injury in transplant-associated thrombotic microangiopathy.
Article in Haematologica, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
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8 authors.
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Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation, marked by excessive complement activation, endothelial injury, and microangiopathy. Although complement blockade benefits some patients, effective prophylactic and therapeutic strategies remain scarce. We, therefore, measured the levels of Krüppel-like factor 4 (KLF4), complement proteins and markers of endothelial injury in plasma samples from 20 TA-TMA patients and 1:1 matched control patients (matched by age, sex, underlying diagnosis, HLA compatibility, graft source, and donor-recipient ABO blood type). The KLF4-mediated regulatory mechanism was delineated through integrated in vitro and in vivo investigations. In this study, plasma analysis revealed that TA-TMA patients exhibit notably lower KLF4 levels compared to matched controls, as well as elevated levels of markers of endothelial injury. In vitro, increased KLF4 expression in human umbilical vein endothelial cells significantly reduced complement deposition and mitigated endothelial damage induced by TA-TMA plasma. Furthermore, KLF4 overexpression notably decreased apoptosis and preserved endothelial barrier integrity. In a mouse model of TA-TMA triggered by dimethyloxalylglycine, upregulation of KLF4 alleviated anemia, thrombocytopenia, and renal complement deposition, while diminishing endothelial inflammatory and thrombotic markers. Intriguingly, pravastatin treatment produced similar improvements. Mechanistic analyses using CUT-Tag, RNA sequencing, luciferase assays, and quantitative real-time polymerase chain reaction revealed that KLF4 binds to the CD46 promoter, enhancing its transcription and thus restraining complement activation in endothelial cells. These results identify KLF4 as a key negative regulator of complement-mediated endothelial injury in TA-TMA. This conclusion is supported by CD46 knockdown abolishing KLF4-mediated benefits, highlighting the therapeutic potential of targeting KLF4 or its downstream effectors, including CD46.
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