Zhang Yan, Lu Xiaohong, Li Ruie, Zhang Jingheng, Peng Jiayu, Li Yafei
Department of Oncology, Luzhou People's Hospital, Luzhou, 646000, Sichuan, China.
Department of Oncology, Luzhou People's Hospital, No. 316, Section 2, Jiu Gu Avenue, Jiangyang District, Luzhou City, 646000, Sichuan Province, China.
J Mol Histol. 2025 Jul 22;56(4):234. doi: 10.1007/s10735-025-10525-0.
Ferroptosis and immune evasion are pivotal mechanisms in the pathogenesis of breast cancer (BC), making them promising therapeutic targets. Phillygenin (PHI), a lignan compound derived from Forsythiae Fructus, has demonstrated broad pharmacological properties, including anti-tumor effects. To discuss the impact of PHI on BC. The study examined PHI's anti-tumor properties and mechanisms using CCK-8 assays, biochemical analyses, DCHF-DA staining, ELISA, immunofluorescence, and western blot techniques. Tumor-bearing mice were utilized for studies in vivo, with tumor tissues being analyzed by H&E staining, immunohistochemistry, and western blotting. The viability of MDA-MB-231 and MCF7 cells was notably repressed by PHI, with respective IC50 values of 81.44 µM and 95.72 µM. PHI elevated intracellular Fe levels, an effect synergistically enhanced by erastin but attenuated by ferrostatin-1. Furthermore, PHI increased reactive oxygen species (ROS) levels while downregulating GPX4 and SLC7A11 expression in both cell lines. PHI also enhanced CD8 T cell cytotoxicity and upregulated IFN-γ and IL-2 levels, but suppressing PD-L1 expression. Mechanistically, PHI repressed the phosphorylation of AKT and GSK3β, along with the β-catenin expression, effects that were reversed by the AKT activator SC79. SC79 also counteracted PHI-induced changes in proliferation, ferroptosis, and immune evasion markers in MDA-MB-231 cells. PHI decreased tumor size and mass, lowered GPX4, p-AKT/AKT, p-GSK3β/GSK3β, and β-catenin levels, and elevated IFN-γ levels in MDA-MB-231 xenograft models. PHI inhibited BC cell proliferation and immune evasion while promoting ferroptosis through suppression of the AKT/β-catenin axis, highlighting its possible as a therapeutic agent for BC.
铁死亡和免疫逃逸是乳腺癌（BC）发病机制中的关键机制，使其成为有前景的治疗靶点。连翘酯苷（PHI）是一种从连翘果实中提取的木脂素化合物，已显示出广泛的药理特性，包括抗肿瘤作用。为探讨PHI对BC的影响。该研究使用CCK-8检测、生化分析、DCHF-DA染色、ELISA、免疫荧光和蛋白质印迹技术研究了PHI的抗肿瘤特性和机制。利用荷瘤小鼠进行体内研究，通过苏木精-伊红染色、免疫组织化学和蛋白质印迹分析肿瘤组织。PHI显著抑制MDA-MB-231和MCF7细胞的活力，IC50值分别为81.44µM和95.72µM。PHI提高细胞内铁水平，这一作用被艾拉司丁协同增强，但被铁死亡抑制剂-1减弱。此外，PHI增加活性氧（ROS）水平，同时下调两种细胞系中GPX4和SLC7A11的表达。PHI还增强CD8 T细胞的细胞毒性，上调IFN-γ和IL-2水平，但抑制PD-L1表达。机制上，PHI抑制AKT和GSK3β的磷酸化以及β-连环蛋白的表达，AKT激活剂SC79可逆转这些作用。SC79还抵消了PHI诱导的MDA-MB-231细胞增殖、铁死亡和免疫逃逸标志物的变化。在MDA-MB-231异种移植模型中，PHI减小肿瘤大小和质量，降低GPX4、p-AKT/AKT、p-GSK3β/GSK3β和β-连环蛋白水平，并提高IFN-γ水平。PHI通过抑制AKT/β-连环蛋白轴抑制BC细胞增殖和免疫逃逸，同时促进铁死亡，突出了其作为BC治疗药物的潜力。
