Zinc is a trace element in human body involved in many biological processes. It is critical for cell growth and acts as a cofactor for the structure and function of a wide range of cellular proteins such as enzymes.Mounting evidence has shown the involvement of intracellular zinc in the bone-related biological processes such as bone growth, homeostasis, and regeneration; however, the molecular mechanism(s) whereby zinc impels tumorigenesis in bone remains largely unexplored. In this article, selective outline related to the content of intracellular zinc in osteosarcoma cells was provided, and its correlation with signalingmolecules that are activated and consequently guide the cells toward tumorigenesis or osteogenesis was discussed. Based on preclinical and clinical evidence, dysregulation of zinc homeostasis, both at intracellular and tissue level, has the main role in the pathogenesis of osteosarcoma. Based on the intracellular zinc content, this element could have a direct role in the dynamics of bone cell transformation and tumor development and play an indirect role in the modulation of the inflammatory and pro/ antitumorigenic responses in immune cells. In this context, zinc transporters and the proteins containing zinc domain are regulated by the availability of zinc, playing a crucial role in bone cell transformation and differentiation. According to recent studies, it seems that intracellular zinc levels could be considered as an early prognosis marker. Besides, identification and targeting of zinc-dependent signaling molecules could tilt the balance of life and death toward the latter in chemoresistant malignant cells and may pave a way for designing of the novel osteosarcoma treatment strategies.

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