CircRNA0052011 modulates DNA damage and repair via FEN1 ubiquitination to mitigate polystyrene nanoplastics-induced genotoxicity in the lung

Polystyrene nanoplastics (PS-NPs) are one type of environmental pollutants that can penetrate biological barriers and accumulate within cells due to their small particle size. This characteristic raises concerns about their potential respiratory toxicity. However, the impact of PS-NPs on genomic stability and the underlying molecular mechanisms remained unclear. We established an in vitro model of PS-NPs-induced DNA damage based on exposure levels detected in human bronchoalveolar lavage fluid (BALF). In this study, we identified a significantly downregulated circRNA, circRNA0052011, and investigated its regulatory role in PS-NPs-induced DNA damage in the lung. We found that exposure to 20 nm PS-NPs significantly downregulated circRNA0052011 expression, leading to impaired DNA repair and increased γ-H2AX expression, a hallmark of DNA damage. Mechanistically, circRNA0052011 directly interacted with flap Endonuclease 1 (FEN1), a key enzyme in the base excision repair (BER) pathway, modulating its ubiquitination and enhancing its protein stability, as revealed by high-throughput Sequencing of circRNAs and proteomic analyses. Overexpression of circRNA0052011 effectively mitigated PS-NPs-induced genotoxicity by preserving FEN1 stability and promoting DNA repair. Furthermore, in vivo experiments validated the protective role of circRNA0052011 against PS-NPs-induced lung injury. These findings provide new insights into the molecular mechanisms of nanoplastics-induced DNA damage and suggest circRNA0052011 as a potential biomarker and therapeutic target for environmental pollutant-related diseases.

CircRNA; DNA damage; Genotoxicity; Nanoplastics; Respiratory toxicity.