GTF2H2 (general transcription factor IIH subunit 2) is a core component of the TFIIH complex with dual roles in transcription and DNA repair. Primary function: GTF2H2 participates in nucleotide excision repair (NER) of damaged DNA and RNA polymerase II transcription initiation, with its N-terminus regulating XPD and C-terminus facilitating RNAP II promoter escape 1. Mechanism: Within TFIIH, GTF2H2 functions to open DNA around lesions for damaged oligonucleotide excision and promotes NER-related genomic stability while regulating cell cycle progression 1. Disease relevance: GTF2H2 variants modify spinal muscular atrophy (SMA) severity, with deletions correlating with improved motor function in pediatric patients 2. Low GTF2H2 expression associates with hepatocellular carcinoma (HCC) development and sex disparities, particularly in males, through impaired NER and altered PAM/NF-κB signaling 1. GTF2H2 dysregulation appears in platinum-resistant ovarian cancer and neuropathic pain pathogenesis 3, 4. Clinical significance: GTF2H2 transcript ratios (ABCC5/GTF2H2, ERCC2/GTF2H2) correlate with cisplatin chemoresistance in lung cancer 5. Tumor-educated platelet-derived GTF2H2 shows diagnostic potential for lung cancer 6. Exosome-derived GTF2H2 exhibits anti-angiogenic properties, suggesting therapeutic potential for HCC treatment 7.