c-Abl tyrosine kinase inhibition attenuate oxidative stress-induced pancreatic β-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 β-cell loss in diabetes mellitus. Recent studies, however, have linked ferroptotic-like death to the β-cell loss in diabetes 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. Mechanistically, treatment with GNF2, a non-ATP competitive c-Abl kinase inhibitor, selectively preserves β-cell function by inducing the orphan nuclear receptor estrogen-related receptor gamma (ERRγ). ERRγ-driven glutaminase 1 (GLS1) expression promotes the elevation of the GSH/GSSG ratio, and this increase leads to the inhibition of lipid peroxidation by GPX4. Strikingly, pharmacological inhibition of ERRγ 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 suppresses the ERRγ agonist DY131-induced GSH/GSSG ratio linked to ferroptotic-like death owing to the loss of GPX4. Furthermore, immunohistochemical analysis showed enhanced ERRγ 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 ERRγ-induced GLS1 expression augments the glutathione antioxidant system, and its downstream signaling leads to improved β-cell function and survival under oxidative stress conditions.
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