8-Oxoguanine modifications in peripheral leukocyte microRNAs promote age-related inflammation by remodeling gene regulatory networks

The role of reactive oxygen species (ROS) in cellular senescence and inflammation has been extensively studied; however, the specific molecular mechanisms underlying these effects have yet to be fully elucidated. By applying a nucleotide pool detection system, oxidative microRNA sequencing, and cytokine chip detection techniques, we found that the levels of 8-oxo-guanosine triphosphate (8-oxo-GTP) increased with age and were positively correlated with elevated levels of oxidized microRNA and increased levels of inflammatory factors. During aging, guanine residues in the seed regions of miR-98-5p that regulates ICAM1, and miR-8085 that regulates CXCL16, were oxidized to 8-oxoguanine. This oxidation weakened the binding affinity of microRNAs to their target genes, thereby promoting the expression of ICAM1 and CXCL16. Oxidized microRNAs can regulate new target genes via o⁸G:A base mismatches. Our findings reveal that ROS-induced oxidative modifications of microRNAs reshape gene regulatory networks, activate inflammatory pathways, providing new insights into the mechanisms of age-related inflammation.