PKNOX2 (PBX/knotted 1 homeobox 2) is a TALE homeodomain transcription factor located on chromosome 11 that functions as a sequence-specific DNA-binding protein regulating transcription through RNA polymerase II 1. The gene encodes a 460-amino acid protein with conserved homeodomains (HR1, HR2) similar to PKNOX1, suggesting capacity to interact with PBX proteins and regulate tissue-specific transcription 1. PKNOX2 plays a critical role in cardiac homeostasis as a suppressor of pathological myocardial fibrosis. In healthy hearts, PKNOX2 is associated with physiological fibroblast activation; however, its expression abnormally decreases during pathological myofibroblast formation in failing hearts 2. Gain-of-function studies improved myocardial fibrosis while knockout aggravated fibrosis in heart failure models, establishing PKNOX2 as a potential therapeutic target 2. Beyond cardiac function, PKNOX2 associates with multiple disease phenotypes. Genome-wide association studies identified PKNOX2 variants as significantly associated with formal thought disorder in schizophrenia 3, alcohol dependence 4, 5, and endocarditis in males 6. PKNOX2 expression is downregulated in bone marrow mesenchymal stem cells from Fanconi anemia patients and responds to TGF-β1 signaling 7. The gene showed selection signatures in Northern Eurasian populations, suggesting roles in adaptation to environmental stress 8.