Gu Tanwei, Dai Fahong, Cai Meiqun, Zhang Xi, Xie Danni, Jiang Huanguo, Tian Lingmin, Yan Liyan, Lan Wenxun, Lv Haitao, Tang Lan, Li Hong, Liu Zhaoguo
Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, 528308, China.
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Sci Rep. 2025 Aug 5;15(1):28552. doi: 10.1038/s41598-025-06179-3.
Hepatic ischemia-reperfusion injury (IRI) is a common complication associated with metabolic disturbances and postoperative liver failure. Despite its prevalence, there is still a significant gap in understanding the changes in hepatic drug-metabolizing enzymes-specifically cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs)-that occur due to hepatic IRI and in identifying effective treatment strategies. This study highlights the temporal changes in the expression and activity of CYPs and UGTs mediated by hepatic ischemia-reperfusion injury, demonstrating a correlation between these enzymatic changes and indicators of liver injury. Our findings demonstrate that Oridonin (ORI), a natural monomer derived from the traditional Chinese medicinal herb Rabdosia rubescens, has notable anti-inflammatory and antioxidant properties. ORI was found to counteract the adverse effects of hepatic IRI on CYPs and UGTs, thus alleviating the metabolic disturbances associated with the injury. Moreover, ORI effectively inhibits inflammatory responses, oxidative stress, and apoptosis related to hepatic IRI. It does this by suppressing the NLRP3 inflammatory pathway, activating the Nrf2 endogenous antioxidant pathway, and modulating the levels of key proteins such as Bcl-2. ORI also demonstrated efficacy in reducing inflammation in a cell hypoxia/reoxygenation (H/R) model. These results suggest that ORI holds promise as a therapeutic candidate for the treatment of hepatic IRI.
肝缺血再灌注损伤（IRI）是一种与代谢紊乱和术后肝衰竭相关的常见并发症。尽管其很常见，但在理解由于肝IRI导致的肝药物代谢酶（特别是细胞色素P450s（CYPs）和尿苷二磷酸葡萄糖醛酸转移酶（UGTs））的变化以及确定有效的治疗策略方面仍存在重大差距。本研究强调了肝缺血再灌注损伤介导的CYPs和UGTs表达及活性的时间变化，证明了这些酶变化与肝损伤指标之间的相关性。我们的研究结果表明，冬凌草甲素（ORI），一种源自传统中药冬凌草的天然单体，具有显著的抗炎和抗氧化特性。发现ORI可抵消肝IRI对CYPs和UGTs的不利影响，从而减轻与损伤相关的代谢紊乱。此外，ORI有效抑制与肝IRI相关的炎症反应、氧化应激和细胞凋亡。它通过抑制NLRP3炎症途径、激活Nrf2内源性抗氧化途径以及调节关键蛋白如Bcl-2的水平来实现这一点。ORI在细胞缺氧/复氧（H/R）模型中也显示出减轻炎症的功效。这些结果表明，ORI有望成为治疗肝IRI的候选治疗药物。
