PHF20L1 is an epigenetic reader protein that recognizes histone post-translational modifications, particularly H3K27me2, through its Tudor and PHD finger domains 1. Its primary function is negative regulation of proteasomal degradation of methylated proteins, including the transcription factors DNMT1 and SOX2 2. PHF20L1 antagonizes SOX2 ubiquitination and proteolysis triggered by MLL1/WDR5 complexes, thereby stabilizing SOX2 and maintaining stem cell pluripotency 2. Mechanistically, PHF20L1 acts as an H3K27me2 reader that recruits polycomb repressive complex 2 (PRC2) and the Mi-2/NuRD complex to coordinate transcriptional repression 3. Clinically, PHF20L1 overexpression drives tumorigenesis across multiple cancers including breast, ovarian, and colorectal cancers 1. In colorectal cancer, PHF20L1 promotes angiogenesis and liver metastasis by negatively regulating HIC1 to enhance PAX2 expression 4. In breast cancer, elevated PHF20L1 correlates with higher histologic grades and distant metastasis-free survival outcomes; PHF20L1 deletion inhibits tumorigenesis in vivo 35. Additionally, PHF20L1 associates with herpesvirus genomes during HSV-1 infection, suggesting roles beyond cancer in viral genome silencing 6. PHF20L1 expression on chromosome 8 is also associated with earlier type 1 diabetes diagnosis age, implicating immune regulation 7. These findings position PHF20L1 as a promising therapeutic target.