Interplay Between Sepsis and Ferroptosis: Unraveling Molecular Insights on Cellular Integrity

Abstract

Sepsis is a complex, life-threatening disease characterized by multiple organ failure due to an abnormal systemic response to infection. Its multifaceted pathophysiology involves a dynamic balance linked pro-inflammatory and anti-inflammatory mediators, coagulation activation, and altered cellular functions. Although different kinds of regulated cell death (RCD) are implicated in sepsis pathogenesis, ferroptosis has emerged as an iron-mediated cell death. Molecular drivers of ferroptosis include iron accumulation, lipid peroxidation, production of reactive oxygen species (ROS), and inhibition of Glutathione peroxidase 4 (GPX4), eventually causing cell death. Current pre-clinical studies are aimed at modulating the ferroptosis pathway, and clinical studies are exploring the therapeutic strategies across diseases. The connection between sepsis and ferroptosis is bound by cellular abnormalities participating in several RCD mechanisms, including apoptosis, pyroptosis, necroptosis, ferroptosis, and autophagy. These cellular abnormalities encompass mitochondrial shrinkage, collapse of cristae, increased membrane density, activation of unfolded protein response, hydrolytic enzyme leakage, and enhanced lysosomal degradation. Additionally, genes associated with ferroptosis, such as Mitogen-Activated Protein Kinase 14 (MAPK14), Acyl-CoA Synthetase Long-Chain Family Member (ACSL4), Ribonucleotide Reductase Regulatory Subunit M2 (RRM2), and GPX4, have altered expression during sepsis, which impacts both the susceptibility and the progression of ferroptotic cell death.