Neutrophil extracellular traps (NETs) play critical roles in hepatic ischemic reperfusion injury (IRI) induced immune responses to inflammation. Diphenyleneiodonium (DPI) is an NADPH oxidative inhibitor that has been implicated in the regulation of NETs formation. However, the effects of NETs and their underlying mechanisms during DPI treatment of acute rejection (AR) after liver transplantation have not been elucidated. This study tested the hypothesis that blocking NETs formation by DPI treatment could be a potential therapeutic target against AR after liver transplantation. NETs were found to be excessively formed within the livers and serum of transplantation models, which could be an independent risk factor for AR. DPI was shown to alleviate hepatic injury and maintain liver functions by inhibiting NETs formation through the nicotinamide adenine dinucleotide phosphate (NADPH)/ROS/peptidylarginine deiminase 4 (PAD4) signaling pathway. NETs are highly involved in AR after liver transplantation. By inhibiting NETs formation, DPI suppresses activation of the NADPH/ROS/PAD4 signaling pathway which acts against AR after liver transplantation. Therefore, DPI is a potential candidate for the therapeutic management of AR after liver transplantation. Combination treatment containing both DPI and tacrolimus revealed a better antidamage efficacy than adjusting either treatment alone, suggesting that the joint therapy might be a promising solution in AR after liver transplantation.

中性粒细胞胞外陷阱 (NETs) 在肝缺血再灌注损伤 (IRI) 诱导的炎症免疫反应中起关键作用。Diphenyleneiodonium (DPI) 是一种 NADPH 氧化抑制剂，与 NETs 形成的调节有关。然而，在 DPI 治疗肝移植后急性排斥 (AR) 期间，NET 的作用及其潜在机制尚未阐明。本研究验证了通过 DPI 治疗阻断 NETs 形成可能是肝移植后抗 AR 的潜在治疗靶点的假设。NETs 被发现在移植模型的肝脏和血清中过度形成，这可能是 AR 的独立危险因素。DPI 通过烟酰胺腺嘌呤二核苷酸磷酸 (NADPH)/ROS/肽基精氨酸脱亚胺酶 4 (PAD4) 信号通路抑制 NETs 的形成，从而减轻肝损伤并维持肝功能。NETs 高度参与肝移植后的 AR。通过抑制 NETs 的形成，DPI 抑制了 NADPH/ROS/PAD4 信号通路的激活，该通路在肝移植后作用于 AR。因此，DPI 是肝移植后 AR 治疗管理的潜在候选者。含有 DPI 和他克莫司的联合治疗显示出比单独调整任何一种治疗更好的抗损伤功效，这表明联合治疗可能是肝移植后 AR 的有希望的解决方案。