Sepsis-Induced Liver Injury Mitigated by Isoferulic Acid Through Inhibition of Hepatic Ferroptosis via the SIRT1 Signaling Pathway.

Abstract

The liver plays a crucial role in the progression of sepsis in patients. Notably, it is the center of metabolism and detoxification, and is important for immune regulation and inflammatory response. Isoferulic acid (IFA), as a phenolic acid compound naturally found in Cimicifuga plants, is recognized for its anti-inflammatory, antioxidant, and free radical-scavenging properties. However, its protective mechanism underlying sepsis-induced acute liver injury remains unknown. The present work focused on examining the effect of IFA on treating sepsis-mediated liver injury and exploring its potential protective mechanism. In the in vivo experiments, the cecal ligation and puncture (CLP) model was used to induce sepsis in mice. EX-527 was administered through intraperitoneal injection, while IFA was given via intragastric administration. Thereafter, hepatic pathological damage was assessed through hematoxylin-eosin staining. Lipid peroxidation levels were determined by measuring MDA, SOD, GSH, and ferrous iron contents. Meanwhile, relevant gene and target protein levels were analyzed using qPCR, immunohistochemistry, and Western blotting. For the in vitro experiments, ferroptosis was induced in AML12 cells with erastin, followed by transfection with SIRT1-siRNA and treatment with IFA. Subsequently, ROS levels were systematically assessed, the extent of mitochondrial membrane potential (MMP) damage was quantified, and Nrf2 immunofluorescence staining analysis was performed in AML12 cells. Finally, molecular docking and surface plasmon resonance (SPR) technologies were applied in confirming the SIRT1-IFA interaction. From the in vivo experiments, sepsis induced by CLP triggered hepatic ferroptosis. While intragastric administration of IFA reduced liver ferroptosis, the intraperitoneal injection of EX-527 combined with intragastric administration of IFA reversed the protective effect of IFA. As revealed by the in vitro experiments, IFA mitigated the erastin-induced ferroptosis of AML12 cells. After transfection with SIRT1-siRNA, the protective effect of IFA was reversed. IFA alleviated the sepsis-induced acute liver injury through the SIRT1 signaling pathway.