ASB4 (ankyrin repeat and SOCS box containing 4) is an E3 ubiquitin ligase that functions as a substrate-recognition component of SCF-like ECS (Elongin-Cullin-SOCS-box protein) complexes 1. Its primary role is promoting vascular differentiation and placental development through oxygen-dependent degradation of ID2, a transcriptional repressor of vascular development 2. ASB4 mediates ubiquitin-dependent proteasomal degradation of target proteins including IRS4, thereby regulating downstream signaling 3. Mechanistically, ASB4 is hydroxylated by FIH (factor inhibiting HIF1α) in an oxygen-dependent manner, enabling its substrate recognition activity during early vascular development when oxygen tension increases 1. In the hypothalamus, ASB4 negatively regulates appetite by modulating melanocortinergic neurons and calcitonin signaling to promote satiety and glucose homeostasis in POMC neurons 3. Clinically, ASB4 loss-of-function associates with preeclampsia pathogenesis. ASB4-null mice develop preeclampsia-like phenotypes including hypertension, proteinuria, and reduced fertility 2. Maternal obesity exacerbates these phenotypes by elevating insulin, which increases ID2 post-transcriptionally, impairing trophoblast differentiation 4. Additionally, genetic variants in ASB4 are associated with human obesity 3, and elevated ASB4 expression correlates with hepatocellular carcinoma migration and invasion 5.