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

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 Fe²⁺ 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, Fe²⁺ 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 Fe²⁺ 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.