ESRP2 is an RNA-binding protein that functions as a splicing regulatory factor controlling the formation of epithelial cell-specific mRNA isoforms. It binds GU-rich sequence motifs in target pre-mRNAs and regulates alternative splicing of genes including FGFR2, CD44, CTNND1, and ENAH 1. ESRP2 acts as a critical regulator of the fetal-to-adult RNA splicing switch; its loss reactivates fetal splicing programs associated with disease pathogenesis. In hepatocellular carcinoma, ESRP2 suppression leads to aberrant TAK1 splicing, generating the oncogenic fetal isoform TAK1_ΔE12 that activates p38MAPK signaling and promotes tumor progression 1. Loss of ESRP2 impairs liver regeneration in alcohol-associated liver disease by dysregulating splicing of targets like Tcf4 and Slk, disrupting WNT and Hippo signaling pathways critical for hepatocyte function 2. In the inner ear, ESRP1/2 regulate mRNA stability of tmc1 and tmc2a, which encode essential mechanotransduction complex components required for hair cell function 3. ESRP2 also regulates craniofacial morphogenesis through CTNND1 splicing; variants affecting this pathway contribute to orofacial clefting 4. Clinically, ESRP2 expression shows complex associations with cancer prognosis. High ESRP2 expression predicts poor outcomes in prostate cancer, correlating with advanced stage and genomic instability 5, whereas suppression drives HCC progression. ESRP2 is downregulated in breast cancer as a consequence of enhancer methylation, with therapeutic implications 6.