DLK2 (delta like non-canonical Notch ligand 2) functions as an inhibitory non-canonical ligand of the NOTCH1 receptor that modulates cellular proliferation and differentiation processes 1. The protein interacts with itself, with DLK1, and with specific EGF-like repeats of NOTCH1's extracellular region, resulting in dose-dependent inhibition of NOTCH signaling 12. Mechanistically, DLK2 binds directly to NOTCH1 and prevents canonical ligand activation, with different expression levels producing opposite biological effects 32. Low DLK2 levels cause slight NOTCH inhibition and enhance cell proliferation and migration, while high levels produce strong NOTCH inhibition, decreased proliferation, and increased apoptosis 2. Disease relevance includes roles in multiple cancers: DLK2 modulates melanoma cell proliferation in a NOTCH-dependent manner 3, serves as a potential prognostic biomarker in clear cell renal cell carcinoma with upregulation associated with poor survival 4, and facilitates hepatocellular carcinoma malignancy through EGFR/PKM2 signaling activation 5. Clinically, DLK2 represents a potential therapeutic target and diagnostic biomarker across various cancer types, with its fine-tuning of NOTCH signaling being critical for controlling tumor growth dynamics 345.