HES4 is a basic helix-loop-helix transcriptional repressor that functions as a negative regulator of transcription by binding N-box DNA motifs 1. During human development, HES4 acts as a direct target of GLI3 in brain organoids, participating in dorsoventral patterning and telencephalic fate decisions 1. In hematopoiesis, HES4 functions downstream of NOTCH1 signaling with non-redundant roles distinct from HES1, promoting early T-cell development while suppressing natural killer and myeloid lineages, though it cannot repress B-cell development 2. HES4 also regulates metabolic processes by repressing genes involved in choline oxidation and serine catabolism, thereby maintaining redox balance and supporting pyrimidine synthesis critical for tumor growth 3. In normal tissues, HES4 is essential for photoreceptor development and survival 4. Pathologically, HES4 plays significant roles in cancer progression: it suppresses epithelial-to-mesenchymal transition in colorectal cancer through interaction with BEST4 5, enforces anti-apoptotic p53 isoform expression in T-cell leukemia downstream of NOTCH1 dimeric signaling 6, and promotes hepatocellular carcinoma immunosuppression via SPP1-mediated immune modulation 7. HES4 elevation is associated with poor prognosis in multiple malignancies and inflammatory diseases 8.