Scheme 1

Left panel: A steady state is characterized by low SIRT6 expression and active PI3K/AKT/mTOR signaling that promotes glycolysis, protein translation, cell growth and survival. Middle panel: MDL-800 activates SIRT6, leading to the inhibition of mTOR, consequently inhibiting glycolysis, protein translation and cell proliferation. MDL-800 activity is attenuated by an upstream feedback loop activating AKT via IGF-1R/IR. Right panel: Blocking PI3K using BYL719 sensitizes cells to MDL-800 treatment and shows superior and synergistic anti-tumor activity. Created in BioRender. Elkabets, M. (2025)/o1ku47s.