The Combined Effects of Circular RNA Methylation Promote Pulmonary Fibrosis.

m 6 A ( N 6 -methyladenosine) is the most common type of RNA methylation modification, mainly occurring on mRNA. Whether m 6 A-modified circular RNAs (circRNAs) are involved in pulmonary fibrosis in different settings remains unclear. Using an m 6 A-circRNA epitranscriptomic chip, candidate circRNAs were selected, among which hsa_circ_0000672 and hsa_circ_0005654 were specifically involved in SiO 2 -induced pulmonary fibrosis by targeting the same protein, eIF4A3, indicating that the m 6 A modification of these two circRNAs has a synergistic effect on fibroblast dysfunction induced by SiO 2 . A mechanistic study revealed that the m 6 A modification of circRNAs was mainly mediated by the methyltransferase METTL3. Furthermore, METTL3 promoted the activation, migration, and activity of pulmonary fibroblasts and participated in SiO 2 -induced pulmonary fibrosis via the circRNA m 6 A modification. m 6 A methylation of circRNAs mediates silica-induced fibrosis, enriching the understanding of circRNAs and uncovering a potential new target for treating fibrosis-related diseases.