DLL4 is a Notch ligand that activates NOTCH1 and NOTCH4 receptors, functioning as a key regulator of vascular development and immune homeostasis. In the vascular system, DLL4 negatively regulates endothelial cell proliferation and migration, suppressing angiogenic sprouting and promoting endothelial quiescence through interdependent signaling with BMP9 1. Beyond angiogenesis, DLL4 plays context-dependent roles in inflammation and disease: in sepsis-induced acute lung injury, DLL4+ neutrophils activate Notch1-mediated endothelial cell death, worsening pathology 2, while in chr15 kidney disease, the uremic toxin indoxyl sulfate triggers proinflammatory macrophage activation through DLL4-Notch signaling 3. DLL4 also contributes to diabetic vasculopathy pathogenesis 4 and promotes cancer stem cell properties and therapy resistance in HER2+ breast cancer 5. In neuroinflammation, astrocytic DLL4-NOTCH1 signaling drives blood-brain barrier disruption via IL-6-STAT3 activation, and blocking DLL4 improves experimental autoimmune encephalomyelitis outcomes 6. Clinically, demcizumab, a DLL4-targeted monoclonal antibody, represents a therapeutic approach, and CAR-T cell therapy targeting DLL4+ tumor cells shows promise in sensitizing chemotherapy-resistant breast cancer. DLL4 also functions in skeletal muscle homeostasis, where its suppression by KLF13 prevents glucocorticoid-induced muscle atrophy 7.