R3HDML (R3H domain containing like) is a secreted protein with emerging roles in skeletal muscle physiology and metabolic disease susceptibility. Primary function: R3hdml regulates satellite cell proliferation and differentiation, which are essential for skeletal muscle development and regeneration 1. During normal muscle development, R3hdml expression increases, and knockout mice exhibit reduced body weight, skeletal muscle mass, and impaired recovery of muscle strength following cardiotoxin-induced injury 1. The protein appears to function through modulation of cell cycle markers, Akt phosphorylation, and insulin-like growth factor signaling within muscle tissue 1. Disease relevance: R3HDML has been identified as a susceptibility locus for type 2 diabetes mellitus in multiple independent populations 234. The locus spans FITM2-R3HDML-HNF4A, with variants associated with T2DM risk in both East Asian and American Indian cohorts 23. Additionally, R3HDML has been implicated in burning mouth syndrome through multivariate genomic analysis 5 and associated with depressive symptoms in schizophrenia 6. R3hdml expression is also altered in drug-induced liver injury contexts 7. Clinical significance: As a metabolically-relevant gene at a validated T2DM locus, R3HDML represents a potential therapeutic target for metabolic and neuropsychiatric conditions.