Antiferroptotic approach for the treatment of diabetes-induced liver pathology: the effects of ethyl pyruvate

Abstract

We showed recently that ferroptosis contributes to liver pathological changes in diabetes. So, targeting of ferroptosis-related pathways could be novel approach for treatment of diabetes- related liver diseases. Ethyl pyruvate (EP) showed antidiabetic action due to anti-oxidative, - inflammatory and -apoptotic properties. We aimed to examine its potential antiferroptotic action in diabetes-related liver pathology. Male Wistar rats were divided into four groups: control; diabetic (STZ, 65 mg/kg); diabetic pre- treated with EP (80 mg/kg/day, starting one week before STZ and continuing following 4 weeks) and diabetic treated with EP, starting with STZ and lasted 4 weeks. Both modes of EP treatment induced attenuation of ferroptotic events in the liver of diabetic rats: accumulation of lipid peroxides (4-HNE), disturbances in iron metabolism (decreased FTH and increased TFR expression), decrease in expression level/activity of ferroptosis- related antioxidative-defense molecules (GPX4, GCL, GSS, Nrf2, HO-1), and activation of ferroptosis-related pro-inflammatory events (HMGB1 nucleus-to-cytosol and NF-kB cytosol-to- nucleus translocation). Those changes reflected on the improvement of diabetes-related morphological alterations such as liver fibrosis and binucleation. Overall, EP interferes with ferroptosis signaling pathways and exerts antiferroptotic activity in the liver in diabetic state. This highlighting the significance of ferroptosis targeting in diabetes- related liver diseases and novel mechanisms/targets of EP beneficial actions.