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FGFR2-regulated cytoskeletal rearrangement disturbs autophagy flux induced by polystyrene nanoplastics
Summary
Researchers found that polystyrene nanoparticles activate the cell-surface receptor FGFR2 in liver cells, triggering cytoskeletal rearrangement that blocks the normal autophagy pathway — the cell's waste-removal system — leading to mitochondrial and lysosomal dysfunction and identifying a previously unknown molecular mechanism for nanoplastic cellular toxicity.
The cytoskeleton, as a fundamental structural component of cells, plays a pivotal role in maintaining cellular architecture and regulating diverse physiological processes. Polystyrene nanoparticles (PS-NPs), emerging as widespread environmental pollutants due to their small size and high mobility, have been reported to exert multiple toxic effects, including neurotoxicity, metabolic toxicity, and immunotoxicity. Nevertheless, research addressing how PS-NPs influence cellular physiological processes through cytoskeletal modulation remains limit. In this study, a model of cytoskeletal damage induced by PS-NPs was established in Hep G2 cells. It was observed that exposure to PS-NPs led to cytoskeletal rearrangement and impaired cell migration. Transcriptome analysis revealed significant alterations in the cytoskeleton regulatory pathways, with fibroblast growth factor receptor 2 (FGFR2) identified as a key upstream regulator. Through a combination of cytoskeleton stabilizer and inhibitor treatments, along with flow cytometry, transmission electron microscopy, and Western blot analyses. The results revealed that mitochondrial and lysosomal functions were compromised, indicating a blockade in autophagic flux. Molecular docking results revealed that PHE713 of the FGFR2 target protein interacted with PS-NPs through Pi-Pi stacking, while also forming a Pi-Alkyl interaction with ALA284, indicating strong binding affinity. Additional RNA interference and overexpression experiments confirmed that PS-NPs activation of FGFR2 triggered cytoskeletal rearrangement, disrupted autophagosome biogenesis, transport, and degradation, and ultimately led to autophagic flux dysregulation. This study provides the first evidence of a molecular mechanism through which PS-NPs influence autophagic flux via FGFR2-mediated cytoskeletal rearrangement, offering new insights into the biological impacts of nanoplastics and their potential environmental health risks.