ZNF558 is a KRAB zinc finger protein transcription factor with critical roles in human brain development and neuronal homeostasis. Primary function: ZNF558 acts as a transcriptional repressor specifically expressed in human forebrain neural progenitor cells 1, where it regulates a gene regulatory network controlling mitochondrial homeostasis. Mechanism: ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to specifically repress SPATA18, a mitophagy-related gene 1. The expression level of ZNF558 is controlled by variable number tandem repeats, with structural variation at this locus influencing developmental timing during early human brain development 1. Disease relevance: ASTN2 deletion associated with psychiatric disorders leads to reduced ZNF558 expression in neuronal cells, resulting in increased SPATA18 expression and mitophagy activity, suggesting ZNF558 mediates a common pathogenic mechanism across psychiatric disorders via mitophagy regulation 2. Additionally, ZNF558 downregulation has been observed in Leber congenital amaurosis patient-derived cells, implicating it in protein degradation and oxidative stress pathways relevant to retinal disease 3. Clinical significance: ZNF558 represents a human-specific evolutionary innovation affecting brain development and may serve as a therapeutic target for psychiatric and neurodegenerative conditions.