Ferroptosis inhibition via the ROS-GPX4 axis drives microplastic-induced malignant progression of nasopharyngeal carcinoma

TL;DR

This study shows that microplastics promote the growth of nasopharyngeal cancer by reducing a type of cell death called ferroptosis, suggesting targeting ferroptosis could help treat microplastic-related cancers.

Contribution

The study identifies a novel mechanism by which microplastics drive cancer progression through ROS-GPX4 axis and ferroptosis inhibition.

Findings

Polystyrene microplastics are internalized by nasopharyngeal carcinoma cells, promoting cancer progression.

Microplastics induce ROS accumulation and activate the NRF2-SLC7A11/GPX4 pathway to suppress ferroptosis.

Restoring ferroptosis with Erastin or RSL3 reverses microplastic-induced malignancy and reduces GPX4 and SLC7A11 expression.

Abstract

Microplastics (MPs), as emerging environmental pollutants, have been closely linked to cancer development and progression. However, their specific role in nasopharyngeal carcinoma (NPC) remains unclear. This study aimed to investigate the potential mechanisms by which polystyrene microplastics (PS-MPs) promote NPC malignancy.

Cellular uptake of PS-MPs was examined by confocal microscopy in NPC cells and NP69. Proliferation, migration, and invasion were evaluated by CCK-8, EdU, colony formation, wound healing, and Transwell assays. In vivo effects were tested in xenograft and lung-metastasis models with PS-MPs exposure via drinking water. Mechanistic investigations included RNA-seq, qRT-PCR, Western blot, ROS detection, immunofluorescence, and pharmacologic interventions with MitoTEMPO and ferroptosis inducers.

PS-MPs were readily internalized by NPC cells, with smaller particles showing higher uptake and NPC cells exhibiting greater uptake than NP69. Functionally, PS-MPs promoted proliferation, migration, invasion, and tumor progression. Mechanistically, they induced modest ROS accumulation, NRF2 nuclear translocation, and upregulation of SLC7A11 and GPX4, thereby suppressing ferroptosis. MitoTEMPO, but not DPI, reduced ROS and attenuated NRF2-SLC7A11/GPX4 signaling, indicating a mitochondrial origin of ROS. Importantly, ferroptosis restoration by Erastin or RSL3 reversed PS-MPs-induced malignant phenotypes and downregulated GPX4 and SLC7A11 expression.

PS-MPs promote NPC progression by generating mitochondrial ROS that activate the NRF2-SLC7A11/GPX4 antioxidant axis and suppress ferroptosis. Pharmacologic reactivation of ferroptosis counteracts these effects, highlighting ferroptosis-targeted therapy as a potential strategy for mitigating microplastic-associated cancer risk.

The online version contains supplementary material available at 10.1186/s12967-025-07508-w.

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