A novel UVA-associated circUBE2I mediates ferroptosis in HaCaT cells

Alternative splicing of precursor messenger RNA (pre-mRNA), including linear splicing and back splicing, produces multiple isoforms that lead to diverse cell fates in response to stimuli including ultraviolet radiation (UVR). Although UVR-induced linear gene splicing has been extensively studied in skin cells, the UVR-induced gene back-splicing events that lead to the production of circular RNAs (circRNAs) have not been thoroughly investigated. The present study used circRNA transcriptome sequencing to screen the differentially expressed circRNAs in human keratinocytes (HaCaT) after UVA irradiation. A total of 312 differentially expressed circRNAs were found in HaCaT cells post-UVR. Among the UVA-induced differentially expressed circRNAs, circUBE2I-a novel circRNA formed by exons 2-6 of the UBE2I gene-was the most significantly upregulated circRNA. RT-qPCR assay further confirmed the increase of circUBE2I level in HaCaT cells after UVA irradiation or H₂O₂ treatment. RNase R digestion experiment revealed the stability of circUBE2I. Overexpression of circUBE2I in keratinocytes induced ferroptosis after UVA or H₂O₂, preventable by the ferroptosis inhibitor ferrostatin-1. Our study provides new insights into the role of circular RNAs in UVA-induced skin cell damage and suggests that circUBE2I could be a therapeutic target in UVR-aroused ferroptosis in skin cells.