The important role of ferroptosis in inflammatory bowel disease

Abstract

Ferroptosis is a type of regulated cell death that occurs due to the iron-dependent accumulation of lethal reactive oxygen species (ROS) from lipids. Ferroptosis is characterized by distinct morphological, biochemical, and genetic features that differentiate it from other regulated cell death (RCD) types, which include apoptosis, various necrosis types, and autophagy. Recent reports show that ferritin formation is correlated to many disorders, such as acute injury, infarction, inflammation, and cancer. Iron uptake disorders have also been associated with intestinal epithelial dysfunction, particularly inflammatory bowel disease (IBD). Studies of iron uptake disorders may provide new insights into the pathogenesis of IBD, thereby improving the efficacy of medical interventions. This review presents an overview of ferroptosis, elucidating its fundamental mechanisms and highlighting its significant involvement in IBD.

Keywords: ROS; ferroptosis; inflammatory bowel disease; intestinal epithelial cells; mechanism.

Figure 1

Mechanism of intracellular ferroptosis. Ferroptosis is defined by iron accumulation, excessive ROS production, and massive lipid peroxidation. Ferroptosis initiation and execution involves three major metabolic pathways: the amino acid/GSH, lipid, and iron pathways. Ferroptosis sensitivity is also controlled via additional signaling pathways and regulators. The following diagram illustrates the ferroptosis process and provides an overview of the key molecules and targets that govern iron and lipid peroxidation regulation. ACSL4 (acyl-CoA synthase long-chain family member 4), BSO (buthionine sulphoximine), DMT1 (divalent metal transporter 1), FSP1 (ferroptosis suppressor protein 1), FPN1 (ferroportin 1) GPX4 (glutathione peroxidase 4) GSH (glutathione), GSSG (oxidized glutathione), GSS (glutathione synthetase), GCL (glutamate-cysteine ligase), LOX (lipoxygenase), LPCAT3 (lysophosphatidylcholine acyltransferase 3), PUFA (polyunsaturated fatty acid), PE (phosphatidylethanolamine), ROS (reactive oxygen species), RSL3 (Ras-selective lethal 3), STEAP3 (six-transmembrane epithelial antigen of prostate 3 metalloreductase), SLC7A11 (solute carrier family 7 member 11), TF (transferrin), TFR1 (transferrin receptor 1), VDAC2/3 (voltage dependent-anion channel 2/3).

Figure 2

Iron metabolism in ferroptosis. Enterocytes absorb iron from the diet through the combined action of iron reductase (e.g., Dcytb) and the divalent metal transporter DMT1. The iron absorbed by the enterocytes is exported to the bloodstream via the ferroportin (FPN-1). At the same time, Fe²⁺ is oxidized to Fe³⁺ by ceruloplasmin. Subsequently, Fe³⁺ is loaded onto the circulating TF in the plasma.

Figure 3

Ferritinosis in IBD. In recent studies, iron uptake disorders have been directly linked to the pathogenesis of IBD. IEC ferroptosis promotes the disruption of epithelial barrier function. As a result, immune cell and cytokine production is hyperactivated, ultimately leading to intestinal inflammation and epithelial damage.