Targeting both ferroptosis and pyroptosis may represent potential therapies for acute liver failure

Abstract

In this editorial, we comment on the article published in the recent issue of the World Journal of Gastroenterology. Acute liver failure (ALF) is a fatal disease that causes uncontrolled massive hepatocyte death and rapid loss of liver function. Ferroptosis and pyroptosis, cell death forms that can be initiated or blocked concurrently, can play significant roles in developing inflammation and various malignancies. However, their roles in ALF remain unclear. The article discovered the positive feedback between ferroptosis and pyroptosis in the progression of ALF, and revealed that the silent information regulator sirtuin 1 (SIRT1) inhibits both pathways through p53, dramatically reducing inflammation and protecting hepatocytes. This suggests the potential use of SIRT1 and its downstream molecules as therapeutics for ALF. Thus, we will discuss the role of ferroptosis and pyroptosis in ALF and the crosstalk between these cell death mechanisms. Additionally, we address potential treatments that could alleviate ALF by simultaneously inhibiting both cell death pathways, as well as examples of SIRT1 activators being used as disease treatment strategies, providing new insights into the therapy of ALF.

Keywords: Acute liver failure; Ferroptosis; Pyroptosis; Crosstalk; Silent information regulator sirtuin 1; P53; Glutathione peroxidase 4; Gasdermin D; Treatment

Core Tip: Acute liver failure (ALF) is a life-threatening disease characterized by uncontrolled death of hepatocytes. Ferroptosis and pyroptosis are two recently discovered types of cell death that can occur simultaneously. However, their roles in ALF remain unclear. The findings show that these two cell death pathways work together to advance ALF and suggest that silent information regulator sirtuin 1 (SIRT1) and its downstream molecules could be potential therapeutics for ALF. Therefore, we will discuss the roles and crosstalk of ferroptosis and pyroptosis in ALF. Activation of SIRT1 and suppression of both cell death pathways may offer new insights into therapeutic targets for ALF.