TP53-induced glycolysis and apoptosis regulator (TIGAR) acts as a switch for nephropathy, but its underlying mechanism is still unclear. The purpose of this study was to explore the potential biological significance and underlying mechanism of TIGAR in modulating adenine-induced ferroptosis in human proximal tubular epithelial (HK-2) cells. HK-2 cells under- or overexpressing TIGAR were challenged with adenine to induce ferroptosis. The levels of reactive oxygen species (ROS), iron, malondialdehyde (MDA), and glutathione (GSH) were assayed. Expression of ferroptosis-associated solute carrier family seven-member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) at the level of mRNA and protein were measured by quantitative real-time-PCR and western blotting. The phosphorylation levels of proteins in the mTOR/S6KP70 pathway were determined by western blotting. Adenine overload triggered ferroptosis in HK-2 cells, as evidenced by reduced levels of GSH, SLC7A11, and GPX4, and increased levels of iron, MDA, and ROS. TIGAR overexpression repressed adenine-induced ferroptosis and induced mTOR/S6KP70 signaling. Inhibitors of mTOR and S6KP70 weakened the ability of TIGAR to inhibit adenine-induced ferroptosis. TIGAR inhibits adenine-induced ferroptosis in human proximal tubular epithelial cells by activating the mTOR/S6KP70 signaling pathway. Therefore, activating the TIGAR/mTOR/S6KP70 axis may be a treatment for crystal nephropathies.