GTF2H3 is a core component of the TFIIH complex, which functions in two critical cellular processes: general and transcription-coupled nucleotide excision repair (NER) of damaged DNA, and RNA transcription by RNA polymerase II. In NER, TFIIH opens DNA around lesions to facilitate excision of damaged oligonucleotides and replacement with new DNA fragments 1. In transcription, GTF2H3 plays an essential role in transcription initiation by enabling promoter opening and promoter escape when the pre-initiation complex is established. GTF2H3 dysfunction is implicated in multiple pathological contexts. A homozygous GTF2H3 mutation (p.Ser222Pro) was identified in consanguineous brothers with nonobstructive azoospermia, suggesting its role in spermatogenesis through vitamin A signaling 2. Genetic variants in GTF2H3 are associated with increased risk of esophageal squamous cell carcinoma in Chinese populations 3. Additionally, GTF2H3 downregulation contributes to anticancer effects in triple-negative breast cancer through suppression of NER pathways 1. GTF2H3 appears dysregulated in advanced Parkinson's disease through miRNA-mediated mechanisms 4 and in leukemic cells with altered Gfi-1B signaling 5. These findings position GTF2H3 as a multifunctional regulator with implications for cancer, neurodegeneration, and male infertility.