Liu Yan, Qi Feng, Xiang Lun-Jian, Yi Zhu-Jun, Li Sheng-Wei
Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Hepatobiliary Surgery, Chongqing University Three Gorges Hospital, Chongqing, China.
Front Pharmacol. 2025 Feb 3;16:1539744. doi: 10.3389/fphar.2025.1539744. eCollection 2025.
Donation after circulatory death (DCD) livers are limited by mandatory warm ischemia and are more susceptible to ischemia‒reperfusion injury (IRI). Inflammation and oxidative stress play key roles in the development of hepatic IRI, and Rutaecarpine (Rut) has anti-inflammatory and anti-oxidative stress effects. The aim of this study was to investigate whether Rut can alleviate hepatic IRI in liver transplantation (LT) and to explore the underlying mechanisms.
Rat DCD LT and oxygen-glucose deprivation/reoxygenation (OGD/R) cell models were established to clarify the effect of Rut on hepatic IRI. The key molecules involved in the hepatoprotective effects of Rut were identified through joint analysis of data from LT patients and drug targets. The target was further validated by , and experiments.
Rut significantly alleviated liver dysfunction, pathological injury, and apoptosis and improved the survival rate of the rats subjected to LT. In addition, Rut significantly inhibited inflammatory response and oxidative stress. Rut also had similar effects on OGD/R-induced hepatocyte injury. Mechanistically, bioinformatics analysis and and experiments revealed that PDE4B may be a key target by which Rut exerts its protective effect, and molecular docking and cellular thermal shift assay confirmed this result. The function of PDE4B was studied gene intervention technology, and the results showed that PDE4B can aggravate hepatic IRI. Furthermore, PDE4B overexpression abrogated the protective effect of Rut on the liver in LT.
Rut alleviates hepatic IRI by targeting PDE4B to inhibit inflammation and oxidative stress. These findings highlight the potential of Rut as a drug candidate for the treatment of patients undergoing LT.
心脏死亡后捐献（DCD）肝脏受到强制性热缺血的限制，更容易发生缺血再灌注损伤（IRI）。炎症和氧化应激在肝脏IRI的发生发展中起关键作用，吴茱萸次碱（Rut）具有抗炎和抗氧化应激作用。本研究旨在探讨Rut是否能减轻肝移植（LT）中的肝脏IRI，并探索其潜在机制。
建立大鼠DCD LT和氧糖剥夺/复氧（OGD/R）细胞模型，以阐明Rut对肝脏IRI的影响。通过对LT患者数据和药物靶点的联合分析，确定参与Rut肝脏保护作用的关键分子。通过……、……和……实验进一步验证该靶点。
Rut显著减轻了肝功能障碍、病理损伤和细胞凋亡，提高了接受LT大鼠的存活率。此外，Rut显著抑制炎症反应和氧化应激。Rut对OGD/R诱导的肝细胞损伤也有类似作用。机制上，生物信息学分析以及……和……实验表明，PDE4B可能是Rut发挥保护作用的关键靶点，分子对接和细胞热位移分析证实了这一结果。采用基因干预技术研究PDE4B的功能，结果表明PDE4B可加重肝脏IRI。此外，PDE4B过表达消除了Rut对LT中肝脏的保护作用。
Rut通过靶向PDE4B抑制炎症和氧化应激来减轻肝脏IRI。这些发现突出了Rut作为治疗LT患者候选药物的潜力。
