KLHL12 (kelch like family member 12) functions as a substrate-specific adapter of the BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex with multiple roles in cellular regulation. Mechanistically, KLHL12 primarily acts by mediating monoubiquitination of SEC31A/B proteins to regulate COPII vesicle coat size, thereby controlling collagen export essential for embryonic stem cell division and neural crest specification 1. The complex also negatively regulates Wnt signaling through ubiquitin-mediated proteolysis of DVL3 [UniProt reference]. Additionally, KLHL12 mediates polyubiquitination of dopamine D4 receptor and PEF1 without triggering protein degradation, with specificity for certain D4R polymorphic variants implicated in attention deficit hyperactivity disorder 2. Clinically, KLHL12 dysfunction associates with multiple pathologies. In cancer, KLHL12-mediated collagen secretion promotes epithelial-mesenchymal transition and tumor metastasis when LZTR1, a competing CUL3 adaptor, is deficient 3. In primary biliary cirrhosis, anti-KLHL12 autoantibodies serve as novel diagnostic biomarkers, particularly valuable for AMA-negative patients, improving diagnostic sensitivity when combined with conventional markers 45. Recent evidence implicates KLHL12 in reticulophagy, where it ubiquitinates RTN3L to target ERAD-resistant misfolded protein condensates for autophagic degradation at ER-reticulophagy sites 6. MEF2B lymphoma-associated mutations escape KLHL12-mediated degradation, enhancing stability and driving B-cell lymphomagenesis 7.