Gu Yulei, Li Yue, Zhang Chao, Liu Yi, Shi Huiting, Tian Xiaoxu, Du Jiaqi, Zhang Hao, Cao Shengli, Gao Lu, Zhang Yanzhou, Zhao Guojun
Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Henan, China.
Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, China.
Transplantation. 2025 Jan 13;109(6):e297-310. doi: 10.1097/TP.0000000000005305.
Hepatic ischemia/reperfusion (I/R) injury (HIRI) is an intrinsic phenomenon observed in the process of various liver surgeries. Unfortunately, there are currently few options available to prevent HIRI. Accordingly, we aim to explore the role and key downstream effects of B-cell lymphoma 6 (BCL6) in hepatic I/R (HIR).
BCL6 expression levels were measured in I/R liver tissue and primary hepatocytes stimulated by hypoxia/reoxygenation (H/R). Moreover, we ascertained the BCL6 effect on HIR in vivo using liver-specific BCL6 knockout mice and adenovirus-BCL6-infected mice. RNA-sequencing, luciferase, chromatin immunoprecipitation, and interactome analysis were combined to identify the direct target and corresponding molecular events contributing to BCL6 function. DNA pull-down was applied to identify upstream of BCL6 in the H/R challenge.
HIR represses BCL6 expression in vivo and in vitro. Hepatic BCL6 overexpression attenuates inflammation and apoptosis after I/R injury, whereas BCL6 deficiency aggravates I/R-induced liver injury. RNA-sequencing showed that BCL6 modulated nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 inflammasome signaling in HIRI. Mechanistically, BCL6 deacetylated nuclear factor kappa-B p65 lysine 310 by recruiting sirtuin 1 (SIRT1), thereby inhibiting the nuclear factor kappa-B/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 pathway. Moreover, overexpression of SIRT1 blocked the detrimental effects of BCL6 depletion. Moreover, EX 527, a SIRT1 inhibitor, vanished protection from BCL6 overexpression. Furthermore, transcription factor 7 was found to mediate the transcription regulation of BCL6 on H/R challenge.
Our results provide the first evidence supporting BCL6 as an important protective agent of HIR. This suggests a potential therapeutic approach for HIR.
肝缺血/再灌注（I/R）损伤（HIRI）是在各种肝脏手术过程中观察到的一种内在现象。不幸的是，目前预防HIRI的选择很少。因此，我们旨在探讨B细胞淋巴瘤6（BCL6）在肝I/R（HIR）中的作用及其关键的下游效应。
检测I/R肝组织和缺氧/复氧（H/R）刺激的原代肝细胞中BCL6的表达水平。此外，我们使用肝脏特异性BCL6基因敲除小鼠和腺病毒-BCL6感染的小鼠在体内确定BCL6对HIR的影响。结合RNA测序、荧光素酶、染色质免疫沉淀和相互作用组分析来鉴定有助于BCL6功能的直接靶点和相应的分子事件。应用DNA下拉实验来鉴定H/R刺激下BCL6的上游分子。
HIR在体内和体外均抑制BCL6的表达。肝脏中BCL6的过表达减轻了I/R损伤后的炎症和凋亡，而BCL6的缺乏则加重了I/R诱导的肝损伤。RNA测序表明，BCL6在HIRI中调节含核苷酸结合寡聚化结构域、富含亮氨酸重复序列和pyrin结构域的蛋白3炎性小体信号通路。机制上，BCL通过招募沉默调节蛋白1（SIRT1）使核因子κB p65赖氨酸310去乙酰化，从而抑制核因子κB/含核苷酸结合寡聚化结构域、富含亮氨酸重复序列和pyrin结构域的蛋白3信号通路。此外，SIRT1的过表达阻断了BCL6缺失的有害影响。此外，SIRT1抑制剂EX 527消除了BCL6过表达的保护作用。此外，发现转录因子7介导BCL6在H/R刺激下的转录调控。
我们的结果提供了首个证据支持BCL6作为HIR的重要保护因子。这提示了一种针对HIR的潜在治疗方法。
