Molecular Mechanisms of Ferroptosis and Its Role in Pulmonary Disease

Abstract

Ferroptosis is a new mode of cell death that is characterized by the excessive accumulation of iron and lipid peroxides. It has unique morphological changes and disparate biochemical features and plays an intricate role in many pathophysiological processes. A great deal of researches confirms that ferroptosis can be regulated by numerous molecules through different mechanisms, supporting great potentials for novel pharmacological therapeutics. Recently, several studies reveal that ferroptosis is also closely associated with the initiation and development of respiratory disease. Understanding the specific mechanism, the molecular trait of ferroptosis and their relationship with pulmonary disease could provide significant references regarding effective treatment of these obstinate disease.

Figure 1

The regulatory mechanisms of ferroptosis: (1) iron metabolism mechanism, including HSPB1-TFR1, ATG5/7-NCOA4 pathway, IREB2 pathway, and Keap1-Nrf2 pathway; (2) system Xc-, including Xc-/GSH/GPX4, p53/SLC7A11 pathway, Keap1-Nrf2 pathway, and sulfur transfer pathway (methionine); (3) lipid metabolism mechanism, including p53-SAT1-15LOX pathway, ACSL4, and LPCAT3; (4) MVA pathway and FSP1-CoQ10-NAD(P)H pathway working cooperatively with GPX4 and GSH/GSSG to inhibit phospholipid peroxidation and ferroptosis. Abbreviations—ACSL4: acyl-CoA synthetase long-chain family member 4; ALOX: arachidonate lipoxygenase; AA: arachidonoyl; AdA: adrenoyl; ABCB6: ATP-binding cassette subfamily B member 6; ATG5: autophagy-related 5; ATG7: autophagy-related 7; CoQ10: coenzyme Q10; Cys: cysteine; system Xc-: cysteine/glutamate transporter receptor; DMT1: divalent metal transporter 1; FTH1: ferritin heavy chain 1; FTL: ferritin light chain; FPN: ferroportin; FSP1: ferroptosis suppressor protein 1; Glu: glutamate; GCLC/GCLM: glutamate-cysteine ligase; GSH: glutathione; GSR: glutathione-disulfide reductase; GPX4: glutathione peroxidase 4; GSS: glutathione synthetase; Gly: glycine; HSPB1: heat shock protein beta-1; HO-1: heme oxygenase-1; IREB2: iron-responsive element binding protein 2; Keap1: Kelch-like ECH-associated protein 1; LOX: lipoxygenase; LPCAT3: lysophosphatidylcholine acyltransferase 3; MVA: mevalonate; NADPH: nicotinamide adenine dinucleotide phosphate; Nrf2: nuclear factor erythroid 2-related factor 2; NCOA4: nuclear receptor coactivator 4; GSSG: oxidized glutathione; PL: phospholipid; ROS: reactive oxygen species; STEAP3: six transmembrane epithelial antigen of the prostate 3; SLC7A11: solute carrier family 7 member 11; SAT1: spermidine/spermine N¹-acetyltransferase 1; TF: transferrin; TFR1: transferrin receptor 1; ZIP8/14: zinc-iron regulatory protein family 8/14.