Gss, known as Glutathione synthetase, catalyzes the final step in the synthesis of glutathione (GSH), a well-established antioxidant. GSH is involved in multiple cellular processes, especially those related to antioxidant defense and protection against oxidative stress [1].

In a mouse model with postnatal deletion of Gss using Stra8-Cre (S8), Gss deficiency was found to cause age-related fertility impairment. The 2-month-old S8/Gss-/-male mice had normal fertility due to compensatory increase in GPX4. However, in 8-month-old S8/Gss-/-mice, decline in GPX4 and increase in ALOX15 led to ROS accumulation, lipid peroxidation, and testicular ferroptosis. This affected meiosis and acrosome formation, resulting in aberrant sperm and reduced fertility. These injuries could be rescued by inhibiting ferroptosis [1].

In glioblastoma, functional screening and transcriptome analyses showed that GSS was a potential regulator of radioresistance through ferroptosis. Depletion of GSS enhanced radiotherapy-induced ferroptosis in glioma cells [2].

In liver cancer, RRM2 inhibited ferroptosis by stimulating GSH synthesis via GSS [3].

In summary, Gss plays a crucial role in protecting cells from oxidative stress-related damage. Studies using Gss knockout mouse models have revealed its significance in male fertility, glioblastoma radiotherapy response, and liver cancer ferroptosis suppression, providing insights into potential therapeutic strategies for these conditions.