Deferoxamine attenuates sepsis-induced liver injury by suppressing ferroptosis

Background: The liver is among the organs most frequently damaged during sepsis, and sepsis-induced liver injury is an independent risk factor for early patient mortality. Ferroptosis has been implicated in sepsis-related organ dysfunction; however, its role in sepsis-induced liver injury remains unclear. This study aimed to investigate the role and underlying mechanisms of Ferroptosis in sepsis-associated liver injury.

Methods: A rat sepsis model was established in vivo using cecal ligation and puncture (CLP). In vitro, BRL-3A hepatocytes were exposed to lipopolysaccharide (LPS). Deferoxamine (DFO) was administered prior to model induction. Inflammatory cytokine concentrations and the extent of liver injury were assessed. Ferroptosis-related biomarkers, including ferrous ions (Fe²⁺), prostaglandin-endoperoxide synthase 2 (PTGS2), acyl-CoA synthetase long-chain family member 4(ACSL4), malondialdehyde (MDA), glutathione (GSH) and peroxidase 4 (GPX4) were quantified. Lipid peroxidation was measured using the BODIPY 581/591 C11 fluorescent probe. Mitochondrial function was evaluated using electron microscopy and JC-1 fluorescent probe assays.

Results: (1) In vivo, DFO treatment was found to alleviate systemic inflammation in septic rats and provided protective effects on the liver. It increased the 7-day survival rate, reduced serum levels of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), decreased alanine aminotransferase and aspartate aminotransferase levels, and mitigated histopathological damage in liver tissue. In vitro, DFO treatment enhanced the viability of LPS-stimulated BRL-3A hepatocytes. (2) Ferroptosis was observed to be activated in septic rats as well as in LPS-stimulated BRL-3A hepatocytes. DFO reduced the intracellular concentration of ferrous ions and reduced lipid peroxidation as indicated by decreased PTGS2, ACSL4 and MDA. Furthermore, DFO alleviated mitochondrial damage (manifested as reduced mitochondrial volume, decreased membrane density, reduced cristae and outer membrane rupture, etc.), and mitochondrial function was improved. Finally, DFO elevated the levels of GSH and GPX4, which enhanced the antioxidant capacity of hepatocytes.

Conclusion: Ferroptosis plays a critical role in the pathogenesis of sepsis-induced liver injury. Targeting the activation of Ferroptosis in hepatocytes during sepsis through intervention with DFO may represent a promising therapeutic strategy for the management of this condition.

Deferoxamine; Ferroptosis; Lipid peroxidation; Sepsis-induced liver injury.