GPX4‐Regulated Ferroptosis Mediates S100‐Induced Experimental Autoimmune Hepatitis Associated with the Nrf2/HO‐1 Signaling Pathway

Abstract

Autoimmune hepatitis (AIH) is an inflammatory autoimmune disease of the liver. Oxidative stress triggered by reactive oxygen radicals is a common pathophysiological basis for the pathogenesis of many liver diseases, and ferroptosis is associated with the toxic accumulation of reactive oxygen species. The signaling transduction pathways responsible for iron processing and lipid-peroxidation mechanisms are believed to drive ferroptosis. However, the specific mechanisms regulating ferroptosis remain unclear. The aims of this investigation were to identify the possible effector functions of ferroptosis, based on glutathione peroxidase 4 (GPX4) regulation in an S100-induced autoimmune hepatitis mouse model and hepatocyte injury models. The S100 liver antigen-induced AIH mouse model was used to detect ferroptotic biomarkers using western blotting. Upregulated levels of cyclooxygenase2 (COX2) and Acyl-Coenzyme A synthase long-chain family member 4 (ACSL4) were observed in the S100-induced AIH model group, while levels of GPX4 and ferritin heavy chain 1 (FTH1) were downregulated ( P < 0.05 ). The expression profiles of COX2, ACSL4, GPX4, and FTH1 were restored following the administration of ferrostatin-1. In addition, Nrf2 and HO-1 levels in the S100-induced AIH model mice after treatment with ferrostatin-1 were downregulated compared to the nonferrostatin-1-treated S100-induced AIH model mice ( P < 0.05 ). Moreover, COX2 and ACSL4 levels were significantly upregulated, with significant FTH1 downregulation, in the AIH model mice when liver-specific GPX4 was silenced using AAV8 constructs. These data indicate that inhibition of ferroptosis significantly ameliorated the influence of AIH on the Nuclear factor E2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway, and that ferroptosis may act as an initiator or intermediate mediator leading to AIH.

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

“…The relationship between inflammatory progress and ferroptosis prompted us to investigate whether ferroptosis is involved in the development of autoimmune diseases [12]. In the S100-induced autoimmune hepatitis (AIH) mouse model, ferroptosis caused hepatitis by downregulating glutathione peroxidase 4 (GPX4), and was inhibited by the Ferrostatin-1 mediated Nrf2/ HO-1 signaling pathway [13]. Ferroptosis also exists in concanavalin A-induced AIH [14].…”

Gingerenone A Alleviates Ferroptosis in Secondary Liver Injury in Colitis Mice via Activating Nrf2–Gpx4 Signaling Pathway

“…Gpx4, a downstream gene of Nrf2, has been reported to inhibit the Nrf2 pathway to increase susceptibility to ferroptosis . Many studies have pointed out that ferroptosis can be reduced and that liver disease can be improved by activating the Nrf2 signaling pathway . Therefore, the present study further explored the mechanism by which GA alleviates SLI.…”

Heme induces intestinal epithelial cell ferroptosis via mitochondrial dysfunction in transfusion‐associated necrotizing enterocolitis

“…A recent study showed that excess heme upregulated HO‐1 and promoted cardiac ferroptosis in mice with sickle cell disease 18 . HO‐1 mediated ferroptosis has been involved in the pathogenesis of multiple organ injuries, including myocardial infarction, 31 liver injury, 32,33 diabetis 34,35 retinal pigment epithelium degeneration, 36 and even cancer therapy 37 . Finally, heme‐assisted iron‐related oxidative reactions are associated with mitochondrial ROS and diverse metabolic processes, including heme catabolism in mitochondria, actively driving ferroptosis 23,38 .…”