ZZEF1 (zinc finger ZZ-type and EF-hand domain containing 1) functions as a histone H3 reader that acts as a transcriptional coregulator of Krüppel-like factors. The protein's second ZZ domain binds to the N-terminus of histone H3, accommodating common epigenetic marks, and this interaction is critical for promoting KLF9 and KLF6-mediated gene regulation 1. In pancreatic β cells, ZZEF1 regulates insulin synthesis and β cell stress through ribosomal stress-surveillance pathways by modulating the RQC sensor EDF1, with ZZEF1 deficiency impairing β cell function and contributing to type 2 diabetes pathology 2. Disease relevance extends beyond metabolic dysfunction; a chromosome 17 tandem duplication creating a ZZEF1-ALOX15 fusion gene causes autosomal-dominant macular dystrophy through ALOX15 overexpression driven by the ZZEF1 promoter, leading to retinal disorganization and photoreceptor damage 3. These findings establish ZZEF1 as a multifunctional epigenetic regulator with implications for metabolic and retinal disease, making it a potential therapeutic target for type 2 diabetes and inherited retinal dystrophies.