DLK1, also known as delta-like canonical notch ligand 1, is a maternally imprinted, paternally expressed gene encoding a transmembrane protein. It is a non-canonical NOTCH ligand, playing crucial roles in adipose tissue homeostasis, neurogenesis, and is involved in regulating stem cell pools and tissue differentiation in tissues like brain, muscle, and liver [1,3]. The DLK1-DIO3 imprinted locus where DLK1 is located is of great significance for fetal development, and its deregulation is associated with developmental disorders and malignancies [4].

Genetic defects of DLK1 paternally inherited were identified in four families with nonsyndromic central precocious puberty (CPP) and a metabolic phenotype, highlighting its role in modulating the hypothalamic-pituitary-gonadal axis [1]. In neuroblastoma, proteogenomic analyses revealed DLK1 as a high-confidence candidate immunotherapeutic target, with its high expression directly correlating with a super-enhancer, and an antibody-drug conjugate targeting it showing potent cytotoxicity in xenograft models [2]. In hepatocellular carcinoma, DLK1-directed chimeric antigen receptor T-cell therapy can specifically eliminate DLK1-positive HCC cells in vitro and in vivo [5]. Also, in adrenocortical carcinoma, DLK1 is a novel adrenocortical stem/progenitor cell marker predicting malignancy, and its cleavable ectodomain in serum can aid in diagnosis [6].

In conclusion, DLK1 is essential for normal development and homeostasis, with its dysregulation linked to multiple diseases including central precocious puberty, neuroblastoma, hepatocellular carcinoma, and adrenocortical carcinoma. Studies using genetic models (although not specifically KO/CKO mouse models in the provided references) have been valuable in uncovering its roles in these disease conditions, helping to understand the underlying mechanisms and potentially guiding the development of new therapeutic strategies.