CircDNA2-Educated YTHDF2 Phase Separation Promotes PM_2.5-Induced Malignant Transformation Through the Blunting of...

Substantial epidemiological evidence suggests a significant correlation between particulate matter 2.5 (PM_2.5) and lung cancer. However, the mechanism underlying this association needs to be further elucidated. Circular RNAs (circRNAs) have emerged as an important topic in the field of epigenetics and are involved in various cancers. This study aimed to explore the molecular basis of PM_2.5-induced lung cancer from an epigenetic perspective and identify potential biomarkers. Initially, the construction of a chronic PM_2.5 exposure model confirmed that PM_2.5 exposure promoted the malignant transformation of human bronchial epithelial (HBE) cells. Mechanistically, abnormally upregulated circDNA2 inhibited the tumor suppressor gene growth arrest and DNA damage 45 alpha (GADD45A) mRNA in an N6-methyladenosine (m⁶A)-dependent manner, mediated by YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) after PM_2.5 exposure. Further analyses revealed that circDNA2 can specifically bind to the YTHDF2 LC domain to promote YTHDF2 protein liquid-liquid phase separation (LLPS), providing sufficient evidence linking LLPS and particulate pollutant-induced tumorigenesis. In conclusion, this study provides new insights into the role of circDNA2 in PM_2.5-induced lung cancer and confirms its clinical value as a potential prognostic biomarker for lung cancer.