GLI1 (GLI family zinc finger 1) functions as a transcriptional activator and serves as the nuclear mediator of the Hedgehog signaling pathway, regulating genes essential for cell growth, differentiation, and tumor development 1. The protein exists in multiple isoforms with distinct functions, including a truncated variant (tGLI1) that exhibits gain-of-function properties and promotes more aggressive cancer phenotypes 1. GLI1 alterations, including gene fusions, amplifications, and rearrangements, define an emerging group of mesenchymal neoplasms characterized by distinctive nested morphology with ovoid cells and rich vascular networks 2. These GLI1-altered tumors occur across various anatomic sites including kidney, uterus, and soft tissues, often presenting diagnostic challenges due to variable morphology and immunophenotype 3. GLI1 immunohistochemistry demonstrates high specificity (98.0%) and sensitivity (91.3%) for identifying mesenchymal neoplasms with driver GLI1 alterations 4. In cancer biology, GLI1 promotes cellular processes including proliferation, migration, invasion, and angiogenesis 1. The protein also mediates peripheral neural remodeling in pancreatic cancer through exosomal circRNA mechanisms 5 and promotes osteogenic transformation in calcific aortic valve disease 6. GLI1 coamplification occurs in approximately 19% of well-differentiated/dedifferentiated liposarcomas, often associated with unique morphological features 7.