8-oxo-7,8-dihydroguanine (8-oxoG), the most frequent form of oxidative-DNA-base lesion caused by ROS, is recognized and repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) through base excision repair (BER) pathway. Beyond its role in DNA repair, OGG1 has been shown to promote transcriptional activation of proinflammatory mediators and contribute to both acute and chronic lung inflammation. However, pioneering studies have shown an anti-inflammation role for OGG1 in inflammatory bowel disease (IBD), but its underlying molecular mechanism remains unclear. In the present study, we unveiled that OGG1 plays an important role in the differentiation of inducible regulatory T cells (iTregs). Binding of OGG1 to 8-oxoG facilitated the recruitment of Smad3 to the promoter, leading to the transcriptional activation. Moreover, OGG1 binding promoted demethylation of CpG sites in the conserved noncoding sequence 2 (CNS2) region of by decreasing Dnmt1 occupancy and enhancing recruitment of Tet1/2. Notably, the S326C variant-a naturally occurring polymorphism in humans-was more effective than the wild-type protein in promoting iTreg differentiation and showed a negative correlation with IBD incidence. Furthermore, treatment with O8, a selective OGG1 inhibitor that blocks base excision activity without affecting substrate binding, significantly alleviated IBD in a mouse model, suggesting a promising therapeutic strategy. Together, these findings extend the understanding of OGG1's epigenetic role in transcriptional regulation and highlight its protective function in inflammatory diseases, potentially shaped by aerobic evolution.