Metabolism　reprogramming　plays　an　important　role　in　tumorigenesis　and　osteosarcoma　metastasis.　Sine　oculis　homeobox　4　(SIX4)　is　reported　to　be　a　key　transcription　factor　that　is　involved　in　glycolysis　reprogramming　of　cancer　cells.　However,　the　role　of　SIX4　in　osteosarcoma　progression　remains　unknown.　The　expression　profile　of　SIX4　in　OS　was　evaluated　in　surgery　samples　of　osteosarcoma　patients.　Functional　studies　were　performed　in　vitro　and　in　vivo.　We　found　that　SIX4　is　significantly　overexpressed　in　osteosarcoma　and　related　to　the　undesirable　prognosis　of　osteosarcoma　patients.　SIX4　promotes　progression　of　osteosarcoma　via　upregulating　isocitrate　dehydrogenase　1　(IDH1),　which　provides　novel　prognostic　biomarkers　and　promising　therapeutic　targets　for　osteosarcoma　patients.