HDGFL2 (hepatoma-derived growth factor-like protein 2) functions as a multifaceted epigenetic regulator with roles in myogenesis, DNA repair, and disease biomarking. In myogenic differentiation, HDGFL2 acts as an epigenetic regulator cooperating with DPF3a to activate myogenic genes by increasing chr19 accessibility through recruitment of SMARCA4/BRG1 to gene promoters 1. The protein preferentially binds chr19 regions marked by repressive histone modifications including H3K9me3, H3K27me3, and H3K36me2 21. Additionally, HDGFL2 promotes DNA double-strand break repair via homologous recombination by facilitating RBBP8 recruitment to damage sites 2, and regulates cellular growth through cyclin D1 expression control 3. Clinically, HDGFL2 has emerged as a significant biomarker for neurodegenerative diseases. Loss of TDP-43-mediated splicing repression produces cryptic HDGFL2 proteins detectable in cerebrospinal fluid and blood of ALS-FTD patients, including presymptomatic C9orf72 mutation carriers, serving as an early diagnostic biomarker 4. Cryptic HDGFL2 accumulates in myonuclei of inclusion body myositis patients, correlating with TDP-43 depletion 5, and appears early during normal aging, preceding TDP-43 inclusions by approximately a decade and associating with cognitive decline 6. HDGFL2 variants also influence drug response in acute myeloid leukemia 7.