SKI is a transcriptional co-repressor with pleiotropic roles in cellular differentiation and genome regulation. Functionally, SKI acts as a negative regulator of TGF-β signaling by interacting with SMAD proteins and transcriptional machinery 1. Beyond TGF-β antagonism, SKI localizes to ribosomal DNA (rDNA) and pericentromeric heterochromatin, where it maintains H3K9 trimethylation and ensures silencing of 45S rRNA genes and satellite DNA—critical for centromere integrity and chromosome 1 2. SKI also functions within mRNA quality control complexes, where it interacts with PELO-HBS1L machinery to regulate ribosomal rescue and cell cycle progression 3. Mechanistically, SKI protein levels are regulated by the ARKADIA E3 ubiquitin ligase, which reciprocally controls TGF-β signaling strength in regulatory T cells 4. Disease relevance spans both developmental and acquired conditions: mutations in SKI-complex components (SKIV2L, TTC37) cause syndromic diarrhea with intractable diarrhea, immunodeficiency, and growth restriction 5, while SKI dysregulation contributes to cancer progression through alterations in proliferation, differentiation, and genome stability 6. In intervertebral disc degeneration, SKI overexpression suppresses fibrosis by inhibiting TGF-β-mediated pathways 1. These findings position SKI as a therapeutic target in cancer and fibrotic diseases.