Abstract Body: Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder and lacks effective medical therapies. Inflammation is a recognized driver of CAVD progression, yet the initiating molecular events that commit valvular cells to an osteogenic fate remain incompletely defined. Telomerase is a multi-subunit complex best known for telomere maintenance, with telomerase reverse transcriptase (TERT) and the RNA component TERC forming its core. TERT is best known for its telomere maintenance functions; however, it can also exhibit transcriptional regulatory functions. The mechanism regulating TERT’s switch from its telomeric role to non-canonical co-transcriptional regulatory functions is not known. Our prior work found that TERT initiates molecular events that drive valvular cell osteogenic differentiation. Mechanistically, TERT promotes RUNX2 expression via interaction with Signal Transducer and Activator of Transcription 5 (STAT5). To enable mechanistic dissection, we used AI-assisted structural modeling to determine TERT-STAT5 interactions and found that TERT’s RNA-binding domain, classically associated with interaction with TERC, also interfaces with STAT5, raising the possibility that dynamic TERT/STAT5 association and physical separation from TERC reflect the functional transition from telomeric activity to non-canonical co-transcriptional regulation. We validated these predictions by developing a real-time tool to visualize TERT/STAT5 interactions in living cells and by determining the dissociation and subcellular distribution of TERT and TERC during osteogenic differentiation. Together, these findings shed light on the underlying mechanism driving osteogenic reprogramming and calcification of valve cells and on a potential therapeutic target to blunt valvular calcification.