KLHL20 (kelch like family member 20) functions as a substrate-binding adapter of the CUL3-RING (BTB-CUL3-RBX1) E3 ubiquitin ligase complex, mediating K33-linked ubiquitination of multiple substrates 1. In apoptosis regulation, KLHL20 mediates ubiquitination and proteasomal degradation of DAPK1, negatively regulating apoptosis 2. KLHL20 regulates autophagy termination by targeting ULK1, PIK3C3/VPS34, and BECN1 for degradation, preventing excessive autophagy and maintaining cellular homeostasis 3. The complex also controls post-Golgi trafficking through K33-linked ubiquitination of CORO7, promoting CORO7-EPS15 interaction and actin polymerization 1. In neurodevelopment, KLHL20 mediates ubiquitination of PDZ-RhoGEF/ARHGEF11, regulating neurite outgrowth 4. Clinically, de novo missense variants in KLHL20's Kelch-type β-propeller domain cause a neurodevelopmental disorder characterized by intellectual disability, epilepsy, autism spectrum disorder, and hyperactivity, with a recurrent variant (p.Gly357Arg) identified in 11 patients 5. In cancer, KLHL20 promotes tumor progression by mediating PML ubiquitination and degradation under hypoxia, potentiating HIF-1 signaling 6. KLHL20 represents a promising therapeutic target for cancer treatment and protein homeostasis disorders 7.