PHF14 is a histone-binding protein that serves as an epigenetic regulator in development and tissue homeostasis. It reads unmodified histone H3 through a bipartite recognition mechanism involving its PHD1-ZnK-PHD2 cassette, with binding sensitive to modifications at specific residues including H3 R2, T3, K4, R8, and K23 1. The protein represses PDGFRA expression and suppresses CDKN1A/p21 to regulate mesenchymal cell proliferation and germinal center B cell differentiation. PHF14 functions within the MeCP2-interacting TCF20/PHF14 chr7 complex, which plays a critical role in epigenetic and transcriptional regulation 2. In development, PHF14 knockout in mice causes neonatal lethality from respiratory failure with severe lung and multi-organ pathology 3, highlighting its importance in organ development. PHF14 has broad cancer associations, with elevated expression correlating with poor prognosis across multiple tumor types. In neurocytomas, PHF14 mutations occur in 14% of cases and its loss increases PDGFRA expression, sensitizing cells to the PDGFR inhibitor sunitinib 4. In colorectal cancer, PHF14 promotes proliferation by supporting DNA damage response complexes, and its knockdown induces apoptosis 5. In glioblastoma and pancreatic ductal adenocarcinoma, PHF14 regulates Wnt/β-catenin signaling to promote growth and metastasis 6, 7. These findings identify PHF14 as a biomarker and therapeutic target in cancer, with evidence supporting PDGFR inhibition as a treatment strategy in PHF14-altered tumors.