Abstract
PM2.5 pollution has been associated with the incidence of lung cancer, but the underlying mechanism is still unclear. PIWI-interacting RNAs (piRNAs), initially identified in germline cells, have emerged as a novel class of small non-coding RNAs (26 - 32 nucleotides) with diverse functions in various diseases, including cancer. However, the role and mechanism of piRNAs in the development of PM2.5-induced lung cancer remain to be clarified. In the presented study, we used a PM2.5-induced malignant transformation cell model to analyze the change of piRNA profiles. Among the disturbed piRNAs, piR-27222 was identified as an oncogene that inhibited cell death in a m6A-dependent manner. Mechanistically, we found that piR-27222 could deubiquitinate and stabilize eIF4B by directly binding to eIF4B and reducing its interaction with PARK2. The enhanced expression of eIF4B, in turn, promoted the expression of WTAP, leading to increased m6A modification in the Casp8 transcript. Consequently, the stability of Casp8 transcripts was reduced, rendering lung cancer cells resistant to PANoptosis. Collectively, our findings reveal that PM2.5 exposure up-regulated piR-27222 expression, which could affect EIF4B/WTAP/m6A axis, thereby inhibiting PANoptosis of cells and promoting lung cancer. Our study provides new insights into understanding the epigenetic mechanisms underlining PM2.5-induced lung cancer.