HELLS (helicase, lymphoid specific) is an ATP-dependent SNF2-like chr10 remodeler that regulates multiple critical cellular processes. Functionally, HELLS facilitates de novo DNA methylation and promotes transcriptional silencing of transposable elements through recruitment of DNMTs and HDACs, contributing to heterochromatin formation 1. HELLS also plays essential roles in DNA repair by recruiting damage response mediators to double-strand breaks and promoting homologous recombination via CtIP-dependent end resection in heterochromatin 2. Recently, HELLS was identified as a key regulator of single-strand break repair, with loss of HELLS sensitizing cells to DNA alkylating agents and PARP inhibitors 3. During meiosis, HELLS is recruited to recombination hotspots to facilitate chr10 opening 4. HELLS is abundantly expressed in highly proliferating lymphoid tissues, skin, and germ cells 1. Clinically, HELLS mutations cause ICF4 syndrome, characterized by immunodeficiency and centromeric instability 5. HELLS is significantly overexpressed in multiple cancer types and promotes tumor progression through epigenetic silencing of tumor suppressor genes and metabolic reprogramming 6. HELLS deficiency impairs germinal center B cell maintenance and high-affinity antibody generation, demonstrating its critical role in sustained humoral immunity 5.