CUL4A is a scaffold protein of cullin-RING E3 ubiquitin ligase complexes that catalyzes the ubiquitination and degradation of target proteins. The complex requires neddylation of CUL4A for activity and associates with substrate recognition components (DCAFs) that determine target specificity. CUL4A participates in diverse cellular processes including DNA repair, cell-cycle regulation, circadian control, and histone deposition through degradation of specific substrates such as CDT1, p53, CRY1, and cyclins D1-D3. Clinically, CUL4A is amplified and overexpressed in breast cancer and linked to poor prognosis 1. In esophageal squamous cell carcinoma, elevated CUL4A promotes proliferation and migration while suppressing necroptosis 2. CUL4A's role in ovarian cancer chemoresistance involves regulation of mitochondrial dynamics and mitophagy; CRL4CUL4A/DDB1 inhibition enhanced mitochondrial fission and mitophagy, sensitizing cells to chemotherapy 3. Conversely, CUL4A is downregulated in pre-eclampsia placentas and its reduction impairs trophoblast migration 4. Thalidomide and its analogues—including lenalidomide, pomalidomide, and iberdomide—exert therapeutic effects in multiple myeloma by binding cereblon (CRBN), which forms an E3 complex with DDB1 and CUL4A; thalidomide inhibits this complex's ubiquitin ligase activity 5. These immunomodulatory drugs have shifted treatment paradigms for hematologic malignancies by exploiting CUL4A-containing complexes.