RCOR3 (REST corepressor 3) is a transcriptional corepressor that functions as a component of histone-modifying complexes regulating gene expression and cell fate determination. RCOR3 interacts with the histone demethylase LSD1 and histone deacetylases HDAC1/2 to form transcriptional repressor complexes 1. However, unlike its paralog RCOR1, RCOR3 distinctly functions as a competitive inhibitor of LSD1-mediated histone H3K4 demethylation, thereby blocking chr1 remodeling and preventing gene silencing 2. This antagonistic activity is due to structural differences in the SANT2 domain 2. RCOR3 exhibits dynamic expression patterns during hematopoietic and neuronal differentiation, with increased levels in mature neurons and opposing erythroid differentiation 23. Clinically, RCOR3 shows dysregulation in disease contexts: promoter hypermethylation and decreased expression occur in advanced sessile serrated adenomas progressing to colorectal cancer 4, and serum RCOR3 levels correlate with liver damage severity in hepatitis B patients 5. RCOR3 protein stability is regulated through PIASγ-mediated SUMOylation 6. These findings position RCOR3 as a specialized corepressor with regulatory roles distinct from RCOR1, controlling epigenetic processes in development and disease.