Sun Liyan, Yang Rui, Hou Xiangmei, Ma Yuehong, Zhang Ziying, Jin Rong, Yi Bing, Jiang Yining, Yan Dayang, Hu Ruiping, Ma Lijie
School of Basic Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China.
School of Basic Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China; Department of Pharmacy and Medical Devices, Jining New Journey Cancer Hospital, Jining, Shandong, China.
Eur J Pharmacol. 2025 Sep 15;1003:177949. doi: 10.1016/j.ejphar.2025.177949. Epub 2025 Jul 15.
Liver injuries are life-threatening conditions accompanied by endoplasmic reticulum stress (ERS). Hydroxysafflor yellow A (HSYA), an active ingredient in the Chinese herbal medicine safflower, has demonstrated protective effects against acute liver injury. This study aimed to investigate the mechanism by which HSYA alleviates liver damage by regulating ERS through the miR-222-3p-PTEN-Wnt axis.
ERS-induced acute liver injury models were established in vitro using tunicamycin-treated BRL-3A cells and in vivo using CCl-treated rats. The protective effects of HSYA against ERS-induced acute liver injury were assessed using the Cell Counting Kit-8 assay for cell viability and flow cytometry assay for cell apoptosis. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed to verify the mRNA and protein expression levels of the ERS markers glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP). To elucidate the regulatory mechanism, the expression of miR-222-3p and Wnt pathway-related markers was measured in both in vitro and in vivo models following HSYA treatment. Additionally, miR-222-3p was transfected into BRL-3A cells to determine the effect of HSYA on ERS and Wnt pathway-related markers and cell apoptosis.
HSYA promoted cell proliferation and decreased cell apoptosis. Compared to tunicamycin, HSYA downregulated GRP78 and CHOP while upregulating PTEN and Axin2 expression. Additionally, it reduced the levels of miR-222-3p, Wnt1, and TCF4 in a dose-dependent manner. However, co-transfection with miR-222-3p diminished these effects.
HSYA exerts hepatoprotective effects by modulating ERS via the miR-222-3p-PTEN-Wnt axis.
肝损伤是危及生命的病症，并伴有内质网应激（ERS）。羟基红花黄色素A（HSYA）是中药红花中的一种活性成分，已显示出对急性肝损伤的保护作用。本研究旨在探讨HSYA通过miR-222-3p-PTEN-Wnt轴调节ERS来减轻肝损伤的机制。
使用衣霉素处理的BRL-3A细胞在体外建立ERS诱导的急性肝损伤模型，使用四氯化碳处理的大鼠在体内建立模型。使用细胞计数试剂盒-8检测细胞活力和流式细胞术检测细胞凋亡来评估HSYA对ERS诱导的急性肝损伤的保护作用。进行逆转录定量聚合酶链反应（RT-qPCR）和蛋白质印迹以验证ERS标志物葡萄糖调节蛋白78（GRP78）和C/EBP同源蛋白（CHOP）的mRNA和蛋白质表达水平。为阐明调节机制，在HSYA处理后的体外和体内模型中测量miR-222-3p和Wnt通路相关标志物的表达。此外，将miR-222-3p转染到BRL-3A细胞中，以确定HSYA对ERS和Wnt通路相关标志物以及细胞凋亡的影响。
HSYA促进细胞增殖并减少细胞凋亡。与衣霉素相比，HSYA下调GRP78和CHOP，同时上调PTEN和Axin2表达。此外，它以剂量依赖性方式降低miR-222-3p、Wnt1和TCF4的水平。然而，与miR-222-3p共转染减弱了这些作用。
HSYA通过miR-222-3p-PTEN-Wnt轴调节ERS发挥肝保护作用。
