HCFC1 (host cell factor C1) is an X-linked transcriptional coactivator that functions as a versatile cofactor in multiprotein transcriptional complexes. Mechanistically, HCFC1 mediates transcription regulation through multiple pathways: it forms complexes with viral proteins (VP16 and POU2F1) during HSV infection to activate immediate-early genes 1, acts as a coregulator for insulin receptor-mediated gene expression at promoters genome-wide 2, and serves as a cofactor for transcription factors including THAP1 to regulate chrX-associated genes 3. HCFC1 also regulates TFEB-dependent transcription of mitophagy genes, with this interaction requiring HSP90 protein stability 4. Disease relevance is substantial. Mutations in HCFC1 cause combined methylmalonic aciduria and homocystinuria (cblX type), phenocopying the more common cblC form through reduced MMACHC expression 5. Beyond metabolic disease, HCFC1 mutations also result in ribosomopathy features due to dysregulation of ribosomal protein genes during development 5. Additionally, HCFC1 dysfunction underlies DYT6 dystonia when its cofactor-binding capacity to THAP1 is disrupted by mutations, leading to transcriptional dysregulation 3. The protein exhibits highest expression in fetal tissues and adult kidney 1, suggesting developmental significance.