Gls2, encoding glutamine synthase 2, is a key regulator of glutaminolysis [1,2,3,4]. Glutaminolysis is an important metabolic pathway, and Gls2's role in it has implications for various biological processes. Gls2 has been linked to pathways such as ferroptosis, a form of cell death characterized by iron-dependent lipid peroxide accumulation, and is also associated with glutamine-glutamate homeostasis [1,3].

Gls2 knockout (KO) mice have provided valuable insights. Gls2 KO mice develop late-occurring B-cell lymphomas and hepatocellular carcinomas (HCC), and in the hepatocarcinogenic STAM protocol, they produce larger HCC tumors than wild-type mice [1]. Gls2 deficiency in cells confers resistance to ferroptosis, as GLS2 promotes ferroptosis by increasing lipid reactive oxygen species (ROS) production through facilitating the conversion of glutamate to α-ketoglutarate (αKG) [1]. In breast cancer, contrary to its general tumor-suppressing role, GLS2 can be protumorigenic, with its knockdown decreasing cell proliferation and its overexpression linked to poor prognosis [5]. Also, Gls2-deficient mice develop accelerated atherosclerosis, suggesting its role in maintaining arterial wall structure through glutamine-glutamate homeostasis [3].

In conclusion, Gls2 has context-dependent functions in different disease areas. In cancer, it can act as a tumor suppressor by promoting ferroptosis in HCC, yet can be protumorigenic in breast cancer. In cardiovascular diseases, Gls2 is involved in preventing atherosclerosis by regulating artery wall remodeling. The study of Gls2 KO mouse models has significantly advanced our understanding of its role in these biological processes and diseases [1,3,5].