PLAG1 is a zinc finger transcription factor that acts as a proto-oncogene by activating target genes including IGFII, CRLF1, CRABP2, CRIP2, and PIGF, driving uncontrolled cell proliferation 1. The gene encodes a DNA-binding transcription activator specific to RNA polymerase II that functions in the nucleus and nucleoplasm. PLAG1 is primarily associated with salivary gland neoplasms, where gene fusions—particularly PLAG1-HMGA2 fusions—are specific for benign pleomorphic adenomas 12. PLAG1 rearrangements also characterize myoepithelial carcinoma, the most common genetic alteration in this malignancy 3. Beyond salivary glands, PLAG1 overexpression drives hepatoblastoma development and is associated with upregulation of IGFII in hepatocellular carcinoma (HCC) 4. In HCC, PLAG1 regulates ferroptosis resistance by transcriptionally controlling GPX4 expression through a PVT1/miR-195-5p regulatory axis, conferring sorafenib resistance 4. In lung cancer, PLAG1 promotes anoikis resistance and metastasis in LKB1-deficient tumors by upregulating glutamate dehydrogenase 1 (GDH1), which activates pro-survival CamKK2-AMPK signaling 5. Monogenic PLAG1 pathogenic variants are rarer causes of Silver-Russell syndrome, distinct from the more common imprinting defects 6.