POLR3D encodes RNA polymerase III (Pol III) subunit D, a peripheral component essential for Pol III-mediated transcription of small non-coding RNAs including 5S rRNA, tRNAs, snRNAs, and miRNAs 12. POLR3D assembles with POLR3E to form a subcomplex that enables Pol III recruitment at transcription initiation sites and drives transcription from type 2 and type 3 promoters, while facilitating efficient termination and reinitiation 123. Beyond its canonical transcriptional role, POLR3D participates in innate immune sensing by transcribing non-self DNA into dsRNA that triggers type I interferon responses via the RIG-I pathway 45. POLR3D expression is subject to epigenetic regulation through miRNA-directed transcriptional silencing, where miR-320 directs AGO1, EZH2, and H3K27me3 deposition at the POLR3D promoter 6. Biallelic pathogenic POLR3D variants cause POLR3-related leukodystrophy, a rare hypomyelinating disorder characterized by developmental delays, cerebellar dysfunction, and systemic features affecting endocrine and skeletal systems, with disease pathology linked to aberrant tRNA homeostasis 78. POLR3D dysfunction has been identified as an independent prognostic factor in osteosarcoma 9.