L3MBTL3 is a methyl-lysine reader protein with dual roles in transcriptional repression and protein degradation. As a negative regulator of Notch signaling, L3MBTL3 binds RBPJ and recruits the demethylase KDM1A to Notch-responsive elements, promoting H3K4me demethylation and transcriptional repression 1. The protein functions as a dimer through its MBT domains to recognize mono- and dimethylated lysine residues 2. Beyond histone regulation, L3MBTL3 acts as an adapter that recruits the CRL4-DCAF5 E3 ubiquitin ligase complex to methylated non-histone proteins including SOX2, DNMT1, and E2F1, promoting their ubiquitin-dependent degradation 3. L3MBTL3 deletion causes DNMT1 accumulation, increased genomic methylation, and embryonic lethality 3. In cancer pathology, L3MBTL3 promotes breast cancer metastasis by interacting with STAT3 and recruiting it to the SNAIL promoter in a methylation-binding-independent manner 4. Genetically, L3MBTL3 polymorphisms associate with cardiometabolic disease susceptibility; specific variants (rs1125970 and rs4897367) reduce coronary heart disease risk in Chinese populations 5. L3MBTL3 also influences adipocyte differentiation, affecting peripheral adipose storage capacity and insulin resistance 6.