c-Abl tyrosine kinase inhibition attenuate oxidative stress-induced pancreatic b-Cell dysfunction via glutathione antioxidant system

Chronic oxidative stress, which is caused by aberrant non-receptor tyrosine kinase (c-Abl) signaling, plays a key role in the progression of beta-cell loss in diabetes mellitus. Recent studies, however, have linked ferroptotic-like death to the beta-cell loss in diabe-tes mellitus. Here, we report that oxidative stress-driven reduced/oxidized glutathione (GSH/GSSG) loss and proteasomal degradation of glutathione peroxidase 4 (GPX4) promote ferroptotic-like cell damage through increased lipid peroxidation. Mechanis-tically, treatment with GNF2, a non-ATP competitive c-Abl kinase inhibitor, selectively preserves beta-cell function by inducing the orphan nuclear receptor estrogen-related receptor gamma (ERRy). ERRy-driven glutaminase 1 (GLS1) expression promotes the elevation of the GSH/GSSG ratio, and this increase leads to the inhibition of lipid peroxi-dation by GPX4. Strikingly, pharmacological inhibition of ERRy represses the expression of GLS1 and reverses the GSH/GSSG ratio linked to mitochondrial dysfunction and increased lipid peroxidation mediated by GPX4 degradation. Inhibition of GLS1 sup-presses the ERRy agonist DY131-induced GSH/GSSG ratio linked to ferroptotic-like death owing to the loss of GPX4. Furthermore, immunohistochemical analysis showed enhanced ERRy and GPX4 expression in the pancreatic islets of GNF2-treated mice compared to that in streptozotocin-treated mice. Altogether, our results provide the first evidence that the orphan nuclear receptor ERRy-induced GLS1 expression aug-ments the glutathione antioxidant system, and its downstream signaling leads to improved beta-cell function and survival under oxidative stress conditions. (Translational Research 2022; 249:74-87)

Automated summary

Chronic oxidative stress plays a key role in beta-cell loss in diabetes, and recent studies have linked this loss to ferroptotic-like death. Oxidative stress leads to the loss of reduced/oxidized glutathione and degradation of glutathione peroxidase 4, promoting lipid peroxidation and ferroptotic-like cell damage. Inhibiting the c-Abl kinase and inducing ERRy preserves beta-cell function by increasing the GSH/GSSG ratio and inhibiting lipid peroxidation. This study provides evidence that ERRy-induced GLS1 expression augments the glutathione antioxidant system, improving beta-cell function and survival under oxidative stress conditions.