PDF(Pubmed)
Abstract：
BACKGROUND: Programmed cell death is an important mechanism for the development of hepatic ischemia and reperfusion (IR) injury, and multiple novel forms of programmed cell death are involved in the pathological process of hepatic IR. ERRFI1 is involved in the regulation of cell apoptosis in myocardial IR. However, the function of ERRFI1 in hepatic IR injury and its modulation of programmed cell death remain largely unknown.
METHODS: Here, we performed functional and molecular mechanism studies in hepatocyte-specific knockout mice and ERRFI1-silenced hepatocytes to investigate the significance of ERRFI1 in hepatic IR injury. The histological severity of livers, enzyme activities, hepatocyte apoptosis and ferroptosis were determined.
RESULTS: ERRFI1 expression increased in liver tissues from mice with IR injury and hepatocytes under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Hepatocyte-specific ERRFI1 knockout alleviated IR-induced liver injury in mice by reducing cell apoptosis and ferroptosis. ERRFI1 knockdown reduced apoptotic and ferroptotic hepatocytes induced by OGD/R. Mechanistically, ERRFI1 interacted with GRB2 to maintain its stability by hindering its proteasomal degradation. Overexpression of GRB2 abrogated the effects of ERRFI1 silencing on hepatocyte apoptosis and ferroptosis.
CONCLUSIONS: Our results revealed that the ERRFI1-GRB2 interaction and GRB2 stability are essential for ERRFI1-regulated hepatic IR injury, indicating that inhibition of ERRFI1 or blockade of the ERRFI1-GRB2 interaction may be potential therapeutic strategies in response to hepatic IR injury.
METHODS: Here, we performed functional and molecular mechanism studies in hepatocyte-specific knockout mice and ERRFI1-silenced hepatocytes to investigate the significance of ERRFI1 in hepatic IR injury. The histological severity of livers, enzyme activities, hepatocyte apoptosis and ferroptosis were determined.
RESULTS: ERRFI1 expression increased in liver tissues from mice with IR injury and hepatocytes under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. Hepatocyte-specific ERRFI1 knockout alleviated IR-induced liver injury in mice by reducing cell apoptosis and ferroptosis. ERRFI1 knockdown reduced apoptotic and ferroptotic hepatocytes induced by OGD/R. Mechanistically, ERRFI1 interacted with GRB2 to maintain its stability by hindering its proteasomal degradation. Overexpression of GRB2 abrogated the effects of ERRFI1 silencing on hepatocyte apoptosis and ferroptosis.
CONCLUSIONS: Our results revealed that the ERRFI1-GRB2 interaction and GRB2 stability are essential for ERRFI1-regulated hepatic IR injury, indicating that inhibition of ERRFI1 or blockade of the ERRFI1-GRB2 interaction may be potential therapeutic strategies in response to hepatic IR injury.
摘要：
背景：程序性细胞死亡是肝缺血和再灌注（IR）损伤发展的重要机制，肝脏IR的病理过程涉及多种新形式的程序性细胞死亡。ERRFI1参与心肌IR细胞凋亡的调控。然而,ERRFI1在肝脏IR损伤中的功能及其对程序性细胞死亡的调控作用尚不清楚.
方法：这里，我们在肝细胞特异性敲除小鼠和ERRFI1沉默肝细胞中进行了功能和分子机制研究,以探讨ERRFI1在肝脏IR损伤中的意义.肝脏的组织学严重程度，酶活性，确定肝细胞凋亡和铁凋亡。
结果：在氧-葡萄糖剥夺/复氧（OGD/R）条件下，IR损伤小鼠肝组织和肝细胞中的ERRFI1表达增加。肝细胞特异性ERRFI1敲除通过减少细胞凋亡和铁凋亡减轻IR诱导的小鼠肝损伤。ERRFI1敲除减少OGD/R诱导的凋亡和铁凋亡肝细胞。机械上,ERRFI1与GRB2相互作用，通过阻止其蛋白酶体降解来维持其稳定性。GRB2的过表达消除了ERRFI1沉默对肝细胞凋亡和铁凋亡的影响。
结论：我们的结果表明，ERRFI1-GRB2相互作用和GRB2稳定性对于ERRFI1调节的肝IR损伤至关重要，表明抑制ERRFI1或阻断ERRFI1-GRB2相互作用可能是响应肝脏IR损伤的潜在治疗策略.
方法：这里，我们在肝细胞特异性敲除小鼠和ERRFI1沉默肝细胞中进行了功能和分子机制研究,以探讨ERRFI1在肝脏IR损伤中的意义.肝脏的组织学严重程度，酶活性，确定肝细胞凋亡和铁凋亡。
结果：在氧-葡萄糖剥夺/复氧（OGD/R）条件下，IR损伤小鼠肝组织和肝细胞中的ERRFI1表达增加。肝细胞特异性ERRFI1敲除通过减少细胞凋亡和铁凋亡减轻IR诱导的小鼠肝损伤。ERRFI1敲除减少OGD/R诱导的凋亡和铁凋亡肝细胞。机械上,ERRFI1与GRB2相互作用，通过阻止其蛋白酶体降解来维持其稳定性。GRB2的过表达消除了ERRFI1沉默对肝细胞凋亡和铁凋亡的影响。
结论：我们的结果表明，ERRFI1-GRB2相互作用和GRB2稳定性对于ERRFI1调节的肝IR损伤至关重要，表明抑制ERRFI1或阻断ERRFI1-GRB2相互作用可能是响应肝脏IR损伤的潜在治疗策略.
