{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cereblon (CRBN) is the substrate‐recognition component of the CRL4 E3 ubiquitin ligase complex that mediates diverse cellular programs through regulated protein degradation. Binding of immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide to CRBN alters its substrate selectivity, thereby promoting the ubiquitination and proteasomal degradation of key regulators including the transcription factors IKZF1 and IKZF3, as well as other proteins such as MEIS2, IRF4, and SALL4. These events underlie both the antitumor efficacy and the teratogenic liability of IMiDs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n Structural studies have further revealed that CRBN contains a distinct drug‐binding pocket that confers enantioselective interactions with these agents, thereby dictating substrate recruitment."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In multiple myeloma and certain B‐cell malignancies, CRBN expression levels and mutational status correlate with clinical response to IMiDs. Reduced CRBN expression or the presence of deleterious mutations is associated with resistance and disease progression, establishing CRBN as a predictive biomarker for therapeutic efficacy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n CRBN is also being exploited in emerging targeted protein degradation strategies; for example, PROteolysis TArgeting Chimeras (PROTACs) have been developed that recruit neosubstrates such as Bruton's tyrosine kinase (BTK) to the CRL4CRBN complex, demonstrating the versatility of CRBN in therapeutic applications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its central role in oncology, CRBN is implicated in neural development and cognitive function. Mutations in the CRBN gene have been linked to forms of autosomal recessive nonsyndromic mental retardation, possibly through dysregulation of substrate degradation that affects ion-channel assembly and neuronal signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "\n Moreover, CRBN regulates key metabolic and signal transduction pathways by targeting substrates such as glutamine synthetase and the AMPK α1 subunit, thereby influencing cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, a large body of evidence positions CRBN as a pivotal regulator of ubiquitin‐mediated proteolysis. Through its capacity to reprogram the substrate specificity of the CRL4 complex in response to small-molecule ligands, CRBN governs processes as diverse as immune modulation, cancer cell viability, metabolic regulation, and neural development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "21"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eric S Fischer, Kerstin Böhm, John R Lydeard, et al. 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