载脂蛋白E调节铁死亡，促使巨噬细胞向M2型极化，并增强甲状腺乳头状癌细胞的迁移和侵袭能力。

APOE modulates ferroptosis to drive macrophage polarization toward the M2 type and enhance PTC migration and invasion.

作者信息

Li Ziwen, Li Min, Sun Sinuo, Bin Yu, Zuo Suwei, Huo Ronghua, Song Jiayin, Xue Gang, Lin Xu, Wu Jingfang

机构信息

Department of Morphology Laboratory, Zhangjiakou Key Laboratory, Hebei North University, Zhangjiakou 075000, China.

Department of Morphology Laboratory, Zhangjiakou Key Laboratory, Hebei North University, Zhangjiakou 075000, China; Department of Otorhinolaryngology Head and Neck Surgery, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, China.

出版信息

Immunobiology. 2025 May;230(3):152900. doi: 10.1016/j.imbio.2025.152900. Epub 2025 Apr 8.

DOI:10.1016/j.imbio.2025.152900

PMID:40245754

Abstract

BACKGROUND

Previous studies have found that Apolipoprotein E (APOE) plays a crucial role in invasion and migration of papillary thyroid carcinoma (PTC) cells and enhance M2 macrophage polarization. Ferroptosis has been implicated in development of various tumors and their treatment resistance, and studies have shown that APOE is involved in ferroptosis regulation. However, whether APOE promotes PTC progression through ferroptosis modulation remains unclear. This study aims to investigate the ferroptosis-related mechanisms through which APOE facilitates cell invasion, migration, and macrophage polarization in PTC.

METHODS

The expression levels of APOE, Sodium-dependent cystine/glutamate exchanger (xCT), Glutathione Peroxidase 4 (GPX4), Ferritin Heavy Chain 1 (FTH1), and Fe in PTC tissues were detected using immunohistochemistry, Prussian blue staining, and western blot. The effects and mechanisms of APOE on ferroptosis were further examined through a series of experiments, including immunofluorescence, electron microscopy, RT-qPCR, western blot, and colorimetric assays. Additionally, In vivo experiments were conducted to assess the effect of APOE silencing on ferroptosis. The interaction between ferroptosis and macrophages in regulating PTC cell invasion and migration was validated using assays.co-culture systems, wound healing assays, and Transwell migration assays.

RESULTS

In PTC tissues, Fe accumulation was lower than in adjacent normal tissues, while the expression of APOE, xCT, GPX4, and FTH1 was significantly higher compared to adjacent normal tissues. Functional assays demonstrated that APOE inhibited ferroptosis in PTC cells, potentially by regulating ferroptosis through the PI3K/AKT1 pathway and modulating Fe accumulation. Furthermore, APOE enhanced the invasion and migration abilities of PTC cells by promoting M2 macrophage polarization via ferroptosis inhibition.

CONCLUSION

This study reveals that APOE regulates ferroptosis through the PI3K/AKT1 pathway, thereby driving macrophage polarization toward the M2 phenotype, which in turn promotes the invasion and migration of PTC.

摘要

背景

先前的研究发现，载脂蛋白E（APOE）在甲状腺乳头状癌（PTC）细胞的侵袭和迁移中起关键作用，并增强M2巨噬细胞极化。铁死亡与各种肿瘤的发生发展及其治疗耐药性有关，研究表明APOE参与铁死亡调节。然而，APOE是否通过调节铁死亡促进PTC进展仍不清楚。本研究旨在探讨APOE促进PTC细胞侵袭、迁移和巨噬细胞极化的铁死亡相关机制。

方法

采用免疫组织化学、普鲁士蓝染色和蛋白质印迹法检测PTC组织中APOE、钠依赖性胱氨酸/谷氨酸转运体（xCT）、谷胱甘肽过氧化物酶4（GPX4）、铁蛋白重链1（FTH1）和铁的表达水平。通过一系列实验，包括免疫荧光、电子显微镜、RT-qPCR、蛋白质印迹和比色测定法，进一步研究APOE对铁死亡的影响及其机制。此外，进行体内实验以评估APOE沉默对铁死亡的影响。使用共培养系统、伤口愈合实验和Transwell迁移实验验证铁死亡与巨噬细胞在调节PTC细胞侵袭和迁移中的相互作用。