Ginsenoside Rb1 alleviated concanavalin A-induced hepatocyte pyroptosis by activating mitophagy.

Pyroptosis is characterized as gasdermin-mediated programmed death and has received substantial attention in recent years. Excessive hepatocyte pyroptosis could induce acute liver injury, and there is a lack of efficient natural compounds to alleviate it. Ginsenoside Rb1 is the most prevalent ginsenoside in ginseng with a variety of biological activities and is usually added to functional foods. In spite of the numerous beneficial effects ginsenoside Rb1 exerts, its role in hepatocyte pyroptosis is yet unknown. In this study, we found that ginsenoside Rb1 alleviated concanavalin A-induced hepatocyte pyroptosis and inhibited NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, which is critical for the process of pyroptosis. Furthermore, with the addition of the mitophagy inhibitor cyclosporin A, we proved that ginsenoside Rb1 promoted PINK1/Parkin-mediated mitophagy to alleviate hepatocyte pyroptosis. The further mechanism was that ginsenoside Rb1 activated mitophagy to eliminate damaged mitochondria. With the clearance of damaged mitochondria, reactive oxygen species production decreased, and then NLRP3 inflammasome expression was inhibited. Our finding demonstrated that ginsenoside Rb1 could alleviate hepatocyte pyroptosis by activating mitophagy, which could provide a basis for formulating effective dietary therapy or dietary recommendation.

SIRT1/mTOR pathway-mediated autophagy dysregulation promotes Pb-induced hepatic lipid accumulation in HepG2 cells.

Lead (Pb) is a common and toxic metal pollutant in the ecological environment and has drawn significant attention due to its presence in various channels, including the use of lead-based paint, mineral extraction and smelting, exhaust gas from gasoline combustion. Autophagy is an essential catabolic pathway and blocked autophagy may result in abnormal lipid metabolism in liver. A body of evidence demonstrates that Pb exposure causes abnormal lipid droplet (LDs) accumulation in the liver, but the mechanism remains unknown. Here, we investigated whether Pb induced lipid accumulation by regulating autophagy in HepG2 cells. In this study, we found that Pb (50 µM) blocked the autophagy flux mainly by transcription factor EB (TFEB)-mediated impairment of lysosome formation and activity. Then we demonstrated that the dense lipid accumulation was observed upon Pb exposure, and induction of autophagy by the autophagy activator rapamycin (Rap) alleviated Pb-induced lipid accumulation, while suppression of autophagy by chloroquine (CQ) exacerbated Pb-induced lipid accumulation, suggested that Pb-induced autophagy blockage might be responsible for lipid accumulation. Moreover, we demonstrated that the SIRT1/mTOR pathway participated in Pb-induced autophagy dysregulation, leading to Pb-induced hepatic lipid accumulation. In summary, these results revealed a new insight into the relationship between Pb-caused autophagy dysregulation and lipid accumulation for the first time and highlight autophagy as a novel therapeutic target against Pb-induced hepatic lipid accumulation which supplying the theoretical basis and potential strategies for the intervention and treatment of Pb-related disease.

Autophagy Inhibition Plays a Protective Role in Ferroptosis Induced by Alcohol via the p62-Keap1-Nrf2 Pathway.

Binge alcohol consumption is a serious health concern. Ferroptosis is an iron-dependent lipid peroxidation mediated cell death. Activation of the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway has been shown to exert a protective effect by blunting the responses to ferroptosis inducers. The autophagy substrate p62 was demonstrated to modulate Nrf2 and contribute to the suppression of ferroptosis. Furthermore, autophagy inhibition resulted in the accumulation of p62, which is a specific substrate for this process. Therefore, we aimed to explore the protective effect of autophagy inhibition against alcohol-induced ferroptosis through activating the p62-Keap1-Nrf2 pathway. Our results demonstrated that alcohol induced ferroptosis, which could be significantly reduced by ferrostatin-1. Additionally, we found that autophagy inhibition could protect HepG2 cells against alcohol-induced ferroptosis by activating the p62-Keap1-Nrf2 pathway. Furthermore, inhibition of autophagy increased the expression of p62, which interacted with Keap1 to promote Nrf2 translocation into the nucleus and upregulation its target proteins ferritin heavy (FTH), ferroportin (FPN), and heme oxygenase-1 (HO-1). This study provides a theoretical basis for further elucidation of the relationship between autophagy and ferroptosis and lays a preliminary foundation for further research concerning dietary guidance in the prevention and treatment of diseases related to alcohol-induced ferroptosis.