MGMT crosspaths with cGAS/STING pathway to regulate innate immune response in macrophage

Transcriptomic profiling demonstrated that stimulation of bone marrow–derived macrophages (BMMs) with the STING agonist DMXAA induced a substantial number of differentially expressed genes (DEGs). Comparative analysis between DMXAA-treated MGMT knockout (KO) and wild-type (WT) BMMs identified a total of 202 DEGs, of which 75 were significantly upregulated genes and 127 were significantly downregulated genes.To elucidate the biological processes underlying these transcriptional alterations, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed on the whole-transcriptome dataset. This analysis revealed enrichment of pathways associated with cellular metabolic activity. Notably, pentose and glucuronate interconversions represented the most positively enriched pathway in DMXAA-stimulated MGMT KO BMMs, whereas linoleic acid metabolism was the most negatively enriched pathway relative to WT cells. Furthermore, Gene Set Enrichment Analysis (GSEA) was conducted using the Hallmark gene set collection. The anaysis showed that the most significantly enriched gene signatures in DMXAA-treated MGMT KO BMMs were associated with IL-6_JAK_STAT3 signaling and hypoxia, underscoring the activation of key inflammatory and stress-response programs under conditions of MGMT deficiency. Overall design: Bone marrow-derived macrophages (BMMs) from WT and MGMT-deficient mice were incubated with 10 mg/ml of STING agonist DMXAA for 24 hours. RNA was extracted from BMMs using RNeasy kit. Total RNA was analyzed by RNA-seq to identify DEGs and pathway enrichment.