Nrf2 ameliorates defective autophagic processes and thereby inhibits ferroptosis in acute pancreatitis by suppressing Beclin1-Slc7a11 complex formation

Abstract

Ferroptosis is a mode of programmed cell death that plays an important role in an increasing number of diseases. Recently, ferroptosis was found to be involved in the pathology of acute pancreatitis (AP). We determined that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the ferroptosis process in AP. By inhibiting Nrf2 expression, the death of acinar cells in AP can be increased. Therefore, to help treat AP to a certain extent, we analyzed the effects of astaxanthin and found that it can activate Nrf2 and reduce the pathological process of AP. The activation of Nrf2 improves defective autophagy in AP and inhibits ferroptosis in acinar cells. Specifically, Nrf2 can promote the expression of Gpx4 and ferritin, and can inhibit the formation of Beclin-Slc7a11 complex by improving autophagy, thereby increasing the membrane expression of Slc7a11. Slc7a11/Gpx4 is an important anti-ferroptosis pathway; Slc7a11 can promote the synthesis of glutathione, while Gpx4 can utilize glutathione to exert antioxidative effects. Thus, we demonstrated that Nrf2 activation not only ameliorated defective autophagy at the time of AP but also promoted membrane expression of Slc7a11 to inhibit ferroptosis in acinar cells, thereby alleviating AP.