Gclc-flox Mouse

Gclc, also known as glutamate-cysteine ligase catalytic subunit, is a key enzyme in the biosynthesis of glutathione (GSH), a crucial antioxidant that maintains intracellular redox homeostasis [5,7,8,9]. It is involved in pathways such as the NRF2-KEAP1-GCLC pathway, which plays a role in cellular response to oxidative stress and is associated with processes like ferroptosis [1,2,3,4,5,9].

In various disease-related studies, Gclc has been shown to be important. In H1N1 virus-infected nasal mucosal epithelial cells, the virus can induce ferroptosis via the NRF2-KEAP1-GCLC pathway, leading to nasal mucosal epithelial inflammation [1]. In cancer, mechanisms such as NSUN2 lactylation enhancing GCLC-dependent glutathione synthesis and SNORA56-mediated pseudouridylation of 28S rRNA promoting GCLC translation are involved in cancer cell resistance to ferroptosis and cancer proliferation [2,3]. In gastric cancer, ACTL6A upregulates GCLC to protect cells from ferroptosis [4]. In non-small-cell lung cancer, GCLC has a non-canonical role in protecting against ferroptosis by maintaining glutamate homeostasis under cystine starvation [5]. In ischemia-reperfusion induced acute kidney injury, Gclc is a potential marker for injured distal nephron, and its inhibition promotes damage to renal tubular epithelial cells [6]. In T cells, Gclc-deficient T cells cannot meet their increased energy and biosynthetic requirements, affecting T cell effector functions [7]. In age-related cataract, preventing GCLC truncation delays cataract formation [8]. In human cancer cells, SIRT2-regulated GCLC desuccinylation helps cells maintain redox balance against oxidative stress-induced ferroptosis [9]. In pancreatic endocrine progenitor cells, Gclc gene deletion causes a severe diabetes phenotype [10].

In conclusion, Gclc is essential for maintaining redox homeostasis, and its functions are implicated in multiple disease conditions such as viral-induced inflammation, cancer, kidney injury, diabetes, and age-related cataract. Studies using gene-knockout or knockdown models have significantly enhanced our understanding of Gclc's role in these biological processes and diseases, providing potential therapeutic targets for these conditions.