Background <p>Osteosarcoma (OS) remains a clinically challenging primary bone tumor because of its strong metastatic potential and unsatisfactory outcomes in advanced cases. Parathyroid hormone receptor 1 (PTHR1), a receptor closely associated with bone-related signaling, has not been fully characterized in OS. This study explored whether PTHR1 contributes to OS progression and clarified the downstream regulatory mechanism involved.</p> Methods <p>Public GEO datasets, clinical OS specimens, and cultured OS cells were used to assess PTHR1 expression. Stable PTHR1 knockdown and overexpression OS cell models were established using lentiviral vectors. Cell growth, apoptosis, motility, invasiveness, EMT, and tumor growth were evaluated by CCK-8, flow cytometry, Transwell, Western blot, and xenograft assays. The underlying mechanism was explored using dual-luciferase reporter assays, ChIP-qPCR, pathway intervention, and rescue experiments.</p> Results <p>PTHR1 was significantly upregulated in OS tissues and cells. PTHR1 overexpression promoted OS cell proliferation, migration, invasion, EMT, and xenograft tumor growth while suppressing apoptosis, whereas PTHR1 knockdown exerted the opposite effects. Mechanistically, PTHR1 activated the cAMP/PKA/CREB1 pathway, leading to transcriptional upregulation of lncRNA PVT1. PVT1 functioned as a competing endogenous RNA by sponging miR-590-3p, thereby relieving miR-590-3p-mediated repression of AXIN2. AXIN2 further promoted EMT and malignant progression, and AXIN2 overexpression partially reversed the inhibitory effects of PTHR1 knockdown.</p> Conclusion <p>PTHR1 promotes OS progression by activating the CREB1/PVT1/miR-590-3p/AXIN2 regulatory axis and enhancing EMT. This five-component signaling cascade may provide potential biomarkers and therapeutic targets for OS.</p> Graphical Abstract <p></p>