RFX5 is a transcription factor that primarily functions as an activator of MHC class II gene expression through recognition and binding to X-box DNA sequences in promoter regions 1. The protein forms a heterotrimeric complex with RFXAP and RFXB, with two RFX5 molecules creating an antiparallel coiled-coil structure that assembles with RFXAP in the cytoplasm before nuclear localization 1. RFX5 demonstrates unique chr1 remodeling capabilities, binding to nucleosomes at superhelical location +2 and inducing DNA distortion that enhances transcriptional accessibility 2. Beyond its classical role in immune regulation, RFX5 coordinates metabolic adaptation with antigen presentation in tissue macrophages by upregulating glutamate dehydrogenase 1 (GLUD1) for glutamine utilization and enhancing HLA-DR surface expression 3. The transcription factor also regulates protocadherin gene clusters involved in neuronal development through modulation of chr1 structure and CTCF binding 4. Clinically, RFX5 deficiency causes severe MHC class II deficiency syndrome, while its expression serves as a prognostic biomarker in stomach adenocarcinoma and correlates with immune infiltration 5. RFX5 emerges as a key regulator linking metabolic stress responses to immune function in autoimmune diseases like rheumatoid arthritis 6.