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已发表论文
EZH2 抑制剂 GSK126 通过 H3K27me3 调节抑制 TLR4 信号传导从而缓解深静脉血栓形成中的血栓炎症反应
Authors Zhou R, Luo J, Zheng H
Received 3 July 2025
Accepted for publication 19 September 2025
Published 2 October 2025 Volume 2025:18 Pages 13519—13534
DOI https://doi.org/10.2147/JIR.S551388
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Qing Lin
Rudan Zhou,1 Ji Luo,2 Hongyu Zheng3
1Xenotransplantation Research Institute, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, People’s Republic of China; 2Department of Intensive Care Unit, West China ZiYang Central Hospital, Ziyang, Sichuan, 641300, People’s Republic of China; 3Department of Trauma Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, People’s Republic of China
Correspondence: Hongyu Zheng, Department of Trauma Center, the First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Wuhua, Kunming, Yunnan, 650032, People’s Republic of China, Tel +86 138 8850 2190, Email zhenghongyu@kmmu.edu.cn
Background: Deep vein thrombosis (DVT) is characterized by abnormal clot formation, often accompanied by endothelial dysfunction and inflammation. Among various inflammatory mediators, extracellular histone H3—acting as a damage-associated molecular pattern (DAMP)—has been implicated in DVT pathogenesis by activating Toll-like receptor 4 (TLR4). Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, regulates gene expression via H3K27me3. Because TLR4 transcription may be epigenetically modulated, this study aimed to evaluate whether GSK126, an EZH2 inhibitor, mitigates DVT by modulating H3K27me3 and suppressing TLR4 signaling.
Methods: To evaluate whether GSK126 attenuates histone H3-exacerbated thromboinflammation in vivo, we employed a stenosis-induced DVT mouse model combined with exogenous histone H3 injection. Tlr4-deficient (Tlr4−/−) mice were used to assess the role of TLR4 signaling in thrombus formation and inflammation. GSK126 was administered intraperitoneally, and thrombus burden along with inflammatory gene expression were quantified. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with lipopolysaccharide (LPS) and treated with GSK126, either alone or in combination with the TLR4-specific inhibitor TAK-242. TLR4 mRNA and protein levels, as well as downstream inflammatory signaling, were analyzed using qPCR and Western blotting.
Results: GSK126 significantly reduced thrombus burden, TLR4 expression, and inflammatory mediators in vivo. In endothelial cells, GSK126 decreased TLR4 and phosphorylated IκBα levels, which was consistently accompanied by reduced H3K27me3 levels. Co-treatment with TAK-242 enhanced these effects. These findings suggest that GSK126 alleviates TLR4-mediated inflammation, likely through its modulation of histone methylation, specifically H3K27me3.
Conclusion: Our results support a role for TLR4 signaling in DVT pathogenesis and suggest that EZH2 inhibition with GSK126 may represent a novel therapeutic approach to thromboinflammation by modulating H3K27me3 and suppressing TLR4-driven inflammatory pathways.
Plain Language Summary: Deep vein thrombosis (DVT) is a serious condition where abnormal blood clots form in veins, often leading to swelling, pain, and sometimes life-threatening complications. Inflammation and immune responses play a major role in the formation of these clots. One key protein involved in this process is TLR4, which is activated by certain molecules released from damaged cells.
In this study, researchers explored whether blocking a specific enzyme called EZH2 could help reduce clot-related inflammation. EZH2 can modify DNA packaging in cells through a marker known as H3K27me3, potentially influencing the activity of TLR4.
The team tested an EZH2 inhibitor called GSK126 in a mouse model of DVT. They found that treatment with GSK126 led to smaller clots and lower levels of TLR4 and other inflammation-related molecules. Similar results were seen in human endothelial cells grown in the lab. When combined with a TLR4-specific blocker, the anti-inflammatory effects were even stronger.
These results suggest that targeting EZH2 using GSK126 may help reduce harmful inflammation in DVT by lowering TLR4 activity. This approach could offer a new potential therapy for patients with clot-related inflammatory diseases in the future.
Keywords: deep vein thrombosis, EZH2, GSK126, TLR4 signaling, H3K27me3, thromboinflammation
1Xenotransplantation Research Institute, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, People’s Republic of China; 2Department of Intensive Care Unit, West China ZiYang Central Hospital, Ziyang, Sichuan, 641300, People’s Republic of China; 3Department of Trauma Center, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, People’s Republic of China
Correspondence: Hongyu Zheng, Department of Trauma Center, the First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Wuhua, Kunming, Yunnan, 650032, People’s Republic of China, Tel +86 138 8850 2190, Email zhenghongyu@kmmu.edu.cn
Background: Deep vein thrombosis (DVT) is characterized by abnormal clot formation, often accompanied by endothelial dysfunction and inflammation. Among various inflammatory mediators, extracellular histone H3—acting as a damage-associated molecular pattern (DAMP)—has been implicated in DVT pathogenesis by activating Toll-like receptor 4 (TLR4). Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, regulates gene expression via H3K27me3. Because TLR4 transcription may be epigenetically modulated, this study aimed to evaluate whether GSK126, an EZH2 inhibitor, mitigates DVT by modulating H3K27me3 and suppressing TLR4 signaling.
Methods: To evaluate whether GSK126 attenuates histone H3-exacerbated thromboinflammation in vivo, we employed a stenosis-induced DVT mouse model combined with exogenous histone H3 injection. Tlr4-deficient (Tlr4−/−) mice were used to assess the role of TLR4 signaling in thrombus formation and inflammation. GSK126 was administered intraperitoneally, and thrombus burden along with inflammatory gene expression were quantified. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with lipopolysaccharide (LPS) and treated with GSK126, either alone or in combination with the TLR4-specific inhibitor TAK-242. TLR4 mRNA and protein levels, as well as downstream inflammatory signaling, were analyzed using qPCR and Western blotting.
Results: GSK126 significantly reduced thrombus burden, TLR4 expression, and inflammatory mediators in vivo. In endothelial cells, GSK126 decreased TLR4 and phosphorylated IκBα levels, which was consistently accompanied by reduced H3K27me3 levels. Co-treatment with TAK-242 enhanced these effects. These findings suggest that GSK126 alleviates TLR4-mediated inflammation, likely through its modulation of histone methylation, specifically H3K27me3.
Conclusion: Our results support a role for TLR4 signaling in DVT pathogenesis and suggest that EZH2 inhibition with GSK126 may represent a novel therapeutic approach to thromboinflammation by modulating H3K27me3 and suppressing TLR4-driven inflammatory pathways.
Plain Language Summary: Deep vein thrombosis (DVT) is a serious condition where abnormal blood clots form in veins, often leading to swelling, pain, and sometimes life-threatening complications. Inflammation and immune responses play a major role in the formation of these clots. One key protein involved in this process is TLR4, which is activated by certain molecules released from damaged cells.
In this study, researchers explored whether blocking a specific enzyme called EZH2 could help reduce clot-related inflammation. EZH2 can modify DNA packaging in cells through a marker known as H3K27me3, potentially influencing the activity of TLR4.
The team tested an EZH2 inhibitor called GSK126 in a mouse model of DVT. They found that treatment with GSK126 led to smaller clots and lower levels of TLR4 and other inflammation-related molecules. Similar results were seen in human endothelial cells grown in the lab. When combined with a TLR4-specific blocker, the anti-inflammatory effects were even stronger.
These results suggest that targeting EZH2 using GSK126 may help reduce harmful inflammation in DVT by lowering TLR4 activity. This approach could offer a new potential therapy for patients with clot-related inflammatory diseases in the future.
Keywords: deep vein thrombosis, EZH2, GSK126, TLR4 signaling, H3K27me3, thromboinflammation