CircNEIL3 mediates pyroptosis to influence lung adenocarcinoma radiotherapy by upregulating PIF1 through miR-1184 inhibition.

Circular RNAs (circRNAs) belong to an abundant category of non-coding RNAs that are stable and specific, and thus have great potential in cancer treatment. However, little is known about the role of circRNAs during radiotherapy in lung adenocarcinoma (LUAD). Here, we established the expression profiles of 1,875 dysregulated circRNAs in non-irradiated and irradiated A549 cells and identified circNEIL3 as a significantly downregulated circRNA in A549 cells treated with 0, 2, or 4 Gy of radiation, respectively. Functional assays demonstrated that circNEIL3 knockdown promoted radiation-induced cell pyroptosis, whereas circNEIL3 overexpression had the opposite effects. Importantly, the effects of circNEIL3 overexpression on inhibiting pyroptosis were reversed by PIF1 knockdown. Mechanistically, circNEIL3-mediated pyroptosis was achieved through directly binding to miR-1184 as a sponge, thereby releasing the inhibition of miR-1184 on PIF1, which ultimately induces DNA damage and triggers AIM2 inflammasome activation. In vivo, circNEIL3 knockdown significantly enhanced the efficacy of radiotherapy as evidenced by decreases in tumor volume and weight. Collectively, the circNEIL3/miR-1184/PIF1 axis that mediate pyroptosis induction may be a novel, promising therapeutic strategy for the clinical treatment of lung cancer.