Chen Kuida, Lu Shipeng, Shi Ke, Ali Mustafa Hussein, Liu Jian, Yin Fangzhou, Yin Wu
State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210023, China.
State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210023, China; Medical Research Center, Northern Jiangsu People's Hospital, Yangzhou, Jiangsu 225001, China.
Int Immunopharmacol. 2025 Jan 3;145:113734. doi: 10.1016/j.intimp.2024.113734. Epub 2024 Dec 10.
Sepsis-induced acute lung injury (ALI) is a life-threatening condition associated with high morbidity and mortality rates in intensive care units (ICUs). Emerging evidence from clinical studies suggests that compounds derived from traditional Chinese medicine (TCM) have shown promising therapeutic effects in treating sepsis-induced ALI. Hyperoside is a bioactive compound extracted from TCM. Prior studies reported that hyperoside exhibits potent anti-inflammatory, antioxidant, and organ-protective properties, however, the underlying mechanisms of its effects on ALI remain unclear. Hyperoside pretreatment significantly reduced inflammation, iron accumulation, and lipid peroxidation in the pulmonary tissues of ALI mice induced by CLP and in LPS-stimulated MLE-12 cells. In particular, hyperoside preferentially binds with Keap1 at Arg380 and Arg415, thereby inhibiting the ubiquitin-mediated degradation of nuclear Nrf2, promoting its translocation to the nucleus, and leading to upregulation of anti-ferroptosis gene expression. Moreover, the protective effects of hyperoside were significantly abrogated after Nrf2 expression was silenced or its activity was inhibited by chemical inhibitors, highlighting that Nrf2 is critically involved in the impact of hyperoside. This study confirms that hyperoside exhibits a therapeutically protective effect against sepsis-induced ALI by inhibiting ferroptosis through Nrf2-mediated signaling pathway. Hyperoside acts as an Nrf2 activator by preferentially binding to Arg380 and Arg415 of Keap1 and disrupting the Keap1/Nrf2 interaction.
脓毒症诱导的急性肺损伤（ALI）是一种危及生命的病症，在重症监护病房（ICU）中具有较高的发病率和死亡率。临床研究的新证据表明，中药衍生的化合物在治疗脓毒症诱导的ALI方面显示出有前景的治疗效果。金丝桃苷是从中药中提取的一种生物活性化合物。先前的研究报道，金丝桃苷具有强大的抗炎、抗氧化和器官保护特性，然而，其对ALI作用的潜在机制仍不清楚。金丝桃苷预处理显著降低了由盲肠结扎穿孔（CLP）诱导的ALI小鼠肺组织以及脂多糖（LPS）刺激的MLE-12细胞中的炎症、铁积累和脂质过氧化。特别是，金丝桃苷优先与Keap1的Arg380和Arg415结合，从而抑制核Nrf2的泛素介导降解，促进其向细胞核的转位，并导致抗铁死亡基因表达上调。此外，在Nrf2表达沉默或其活性被化学抑制剂抑制后，金丝桃苷的保护作用显著消除，这突出表明Nrf2在金丝桃苷的作用中起关键作用。本研究证实，金丝桃苷通过Nrf2介导的信号通路抑制铁死亡，对脓毒症诱导的ALI具有治疗保护作用。金丝桃苷通过优先结合Keap1的Arg380和Arg415并破坏Keap1/Nrf2相互作用，充当Nrf2激活剂。
