PHF2 (PHD finger protein 2) is a histone demethylase that serves as a tumor suppressor through multiple epigenetic mechanisms. PHF2 catalyzes demethylation of histone H3 lysine 9 (H3K9me2) and H4 lysine 20 (H4K20me3), with activity regulated by phosphorylation—PKA phosphorylation activates its enzymatic function 1, while AMPK phosphorylation at S655 enhances H3K9me2 demethylation activity to suppress cancer metastasis 2. PHF2 functions as a coactivator with ARID5B in transcriptional regulation and maintains pericentromeric heterochromatin stability essential for genome integrity and neural progenitor proliferation 3. Beyond histone modification, PHF2 acts as an E3 ubiquitin ligase targeting SREBP1c to suppress lipogenesis in hepatocellular carcinoma 4. Clinically, PHF2 dysfunction associates with multiple malignancies. Down-expression correlates with poor prognosis, lymph node metastasis, and proliferation in breast cancer 5. Inactivating frameshift mutations occur in colorectal and gastric cancers with high microsatellite instability 6. Reduced PHF2 expression driven by risk alleles at locus 9q22.33 promotes nasopharyngeal carcinoma cell proliferation 7. Additionally, PHF2 upregulation contributes to neuroinflammation in Alzheimer's disease; PHF2 knockdown reduces inflammatory gene expression and improves cognitive outcomes 8. Genetic association studies identify PHF2 as a susceptibility locus for irritable bowel syndrome 9.