Human umbilical cord mesenchymal stem cells protect against ferroptosis in acute liver failure through the IGF1-hepcidin-FPN1 axis and inhibiting iron loading

Abstract

Acute liver failure (ALF) is a significant global issue with elevated morbidity and mortality rates. There is an urgent and pressing need for secure and effective treatments. Ferroptosis, a novel iron-dependent regulation of cell death, plays a significant role in multiple pathological processes associated with liver diseases, including ALF. Several studies have demonstrated that mesenchymal stem cells (MSCs) have promising therapeutic potential in the treatment of ALF. This study aims to investigate the positive effects of MSCs against ferroptosis in an ALF model and explore the underlying molecular mechanisms of their therapeutic function. Our results show that intravenously injected MSCs protect against ferroptosis in ALF mouse models. MSCs decrease iron deposition in the liver of ALF mice by downregulating hepcidin level and upregulating FPN1 level. MSCs labelled with Dil are mainly observed in the hepatic sinusoid and exhibit colocalization with the macrophage marker CD11b fluorescence. ELISA demonstrates a high level of IGF1 in the CCL 4 +MSC group. Suppressing the IGF1 effect by the PPP blocks the therapeutic effect of MSCs against ferroptosis in ALF mice. Furthermore, disruption of IGF1 function results in iron deposition in the liver tissue due to impaired inhibitory effects of MSCs on hepcidin level. Our findings suggest that MSCs alleviate ferroptosis induced by disorders of iron metabolism in ALF mice by elevating IGF1 level. Moreover, MSCs are identified as a promising cell source for ferroptosis treatment in ALF mice.

Effect of sulfasalazine on ferroptosis during intestinal injury in rats after liver transplantation

“…Ferrostain-1 is an effective and selective ferroptosis inhibitor. It prevents membrane lipid damage through a reduction mechanism and eliminates lipid ROS produced by the body by inhibiting the enzyme-mediated process catalyzed by iron-dependent lipoxygenase, thereby inhibiting cell death [23][24][25][26][27][28] . SAS is an important drug for the treatment of ulcerative colitis and is also one of the most commonly used anti-inflammatory drugs in clinical practice.…”