TIGAR, short for TP53-induced glycolysis and apoptosis regulator, is a downstream target gene of p53. It contains a sequence similar to the 6-phosphofructose kinase/fructose-2,6-bisphosphatase domain. TIGAR mainly functions as a fructose-2,6-bisphosphatase, hydrolyzing fructose-1,6-diphosphate and fructose-2,6-diphosphate to inhibit glycolysis. This in turn promotes the pentose phosphate pathway to produce NADPH and ribose, reducing intracellular reactive oxygen species (ROS), maintaining energy metabolism balance, and regulating autophagy and stem cell differentiation [3].

In colorectal cancer, knockdown of TIGAR increases erastin-induced ferroptosis, decreases the GSH/GSSG ratio, increases lipid peroxidation, and makes cells more sensitive to ferroptosis, suggesting TIGAR confers ferroptosis resistance via the ROS/AMPK/SCD1 pathway [1]. In murine sepsis models, myeloid Tigar ablation attenuates sepsis by inhibiting inflammation as TIGAR binds to TAK1 and promotes its activation, and interfering with this binding has therapeutic effects [2]. In adipocytes, TIGAR transgenic mice show increased fat mass and obesity-like phenotypes as TIGAR triggers LRRK2-mediated defects in macroautophagy and chaperone-mediated autophagy, while fat-specific TIGAR knockdown alleviates obesity symptoms [4].

In conclusion, TIGAR plays crucial roles in multiple biological processes and disease conditions. Gene-knockout (KO) or conditional-knockout (CKO) mouse models have been instrumental in revealing its functions in cancer, sepsis, and obesity. Understanding TIGAR's functions through these models provides potential therapeutic targets for these diseases.