Deciphering ferroptosis in critical care: mechanisms, consequences, and therapeutic opportunities

Abstract

Ischemia-reperfusion injuries (IRI) across various organs and tissues, along with sepsis, significantly contribute to the progression of critical illnesses. These conditions disrupt the balance of inflammatory mediators and signaling pathways, resulting in impaired physiological functions in human tissues and organs. Ferroptosis, a distinct form of programmed cell death, plays a pivotal role in regulating tissue damage and modulating inflammatory responses, thereby influencing the onset and progression of severe illnesses. Recent studies highlight that pharmacological agents targeting ferroptosis-related proteins can effectively mitigate oxidative stress caused by IRI in multiple organs, alleviating associated symptoms. This manuscript delves into the mechanisms and signaling pathways underlying ferroptosis, its role in critical illnesses, and its therapeutic potential in mitigating disease progression. We aim to offer a novel perspective for advancing clinical treatments for critical illnesses.

Keywords: critical illness; ferroptosis; iron overload; lipid metabolism; mitochondrial dysfunction.

Figure 1

The connection between different diseases and ferroptosis. The connection between different diseases and ferroptosis. Ferroptosis plays a role in the regulation of various systemic diseases, such as diseases of the nervous system, cardiovascular system, digestive system, musculoskeletal system, autoimmune system, visual system, lung, liver, and kidney. Ferroptosis often involves systemic interactions, where iron metabolism and oxidative stress affect multiple organ systems. For example, diseases like sepsis can trigger widespread inflammation and organ failure involving ferroptotic pathways in the liver, lungs, kidneys, and cardiovascular system. Understanding these pathways is essential for developing targeted therapies that can mitigate ferroptosis-induced damage across various diseases.

Figure 2

Molecular interaction diagram related to ferroptosis mechanisms. Key molecules and pathways involved in the process of ferroptosis include iron metabolism, antioxidant responses, lipid peroxidation, and related signaling pathways. Iron metabolism plays a central role in ferroptosis, as the accumulation of iron within cells can catalyze the formation of ROS through the Fenton reaction. Antioxidant Responses include GSH, GPX4, NADPH and FAD. Serve as electron donors in the regeneration of GSH and other antioxidants, supporting the cellular antioxidant response to counteract ferroptosis. Lipid peroxidation is a hallmark of ferroptosis, involving the oxidative degradation of PUFAs in cellular membranes. ABCA1, ATP-binding cassette transporter A1; Acetyl CoA, Acetyl coenzyme A; ACSL4, Acyl-CoA synthetase long-chain family member 4; AMPK, AMP-activated protein kinase; α-KG, Alpha-Ketoglutarate; Cys, Cysteine; E-cadherin, Epithelial cadherin; EMP1, Epithelial membrane protein-1; Fe³⁺, Iron ion (trivalent); Fe²⁺, Iron ion (divalent); FTL/KGM, Ferritin light chain/keratinocyte growth factor; FTH1, Ferritin heavy chain 1; Gln, Glutamine; Glu, Glutamate; GLS, Glutaminase; GPX4, Glutathione peroxidase 4; GSH, Glutathione; HMG-CoA, 3-Hydroxy-3-methylglutaryl coenzyme A; HO-1, Heme oxygenase 1; IPP, Isoprenoid pyrophosphate; LPCAT3, Lysophosphatidylcholine acyltransferase 3; Mevalonate, Mevalonic acid; MUFA, Monounsaturated fatty acid; NCOA4, Nuclear receptor coactivator 4; NF2, Neurofibromin 2; NOX4, NADPH oxidase 4; NRF2, Nuclear factor erythroid 2-related factor 2; P53, Tumor protein P53; PL-OOH, Phospholipid hydroperoxide; PUFA, Polyunsaturated fatty acid; PUFA-CoA, Polyunsaturated fatty acid coenzyme A; ROS, Reactive oxygen species; SCD1, Stearoyl-CoA desaturase-1; SREBP2, Sterol regulatory element-binding protein 2; System Xc^-, Cystine/glutamate antiporter; TAZ, Transcription coactivator with PDZ-binding motif; TGase, Transglutaminase; TCA cycle, Tricarboxylic acid cycle; YAP, Yes1-associated transcriptional regulator.

Figure 3

Ferroptosis mediates a variety of ischemia-reperfusion injuries. Ferroptosis, a unique regulated cell death form, mediates various IRIs. During ischemia, restricted blood supply causes hypoxia, disrupting metabolism and leading to intracellular changes like ROS generation in mitochondria’s electron transport chain. Reperfusion restores blood flow but worsens oxidative stress. Increased ROS overwhelms antioxidant systems like GPX4, triggering ferroptosis. Abundant tissue iron ions in the ROS-influenced Fenton reaction generate hydroxyl radicals, initiating lipid peroxidation. This is key in ferroptosis. In organs like the heart, brain, kidneys, and liver, ferroptosis-caused lipid metabolism disruption and peroxide accumulation damage cell membranes, causing cell death. Thus, ferroptosis-mediated damage in ischemia-reperfusion contributes to tissue dysfunction and organ failure. ACSL4, Acyl-CoA synthetase long-chain family member 4; ALR, Augmenter of liver regeneration; ATF3, Activating transcription factor 3; DFO, Deferoxamine; DFP, Deferiprone; Fe²⁺, Iron ion; Fer-1, Ferrostatin-1; FTH, Ferritin heavy chain; GPX4, Glutathione peroxidase 4; GSH, Glutathione; HIF, Hypoxia-inducible factor; IASPP, Inhibitor of apoptosis stimulating protein of p53; Lip-1, Liproxstatin-1; IRI, Ischemia-reperfusion injury; NAC, N-acetylcysteine; NRF2, Nuclear factor erythroid 2-related factor 2; PTGS2, Prostaglandin-endoperoxide synthase 2; ROS, Reactive oxygen species; ShRNA, short hairpin RNA lentivirals; SLC7A11, Solute carrier family 7 member 11; STAT3, Signal transducer and activator of transcription 3; System Xc^-, Cystine/glutamate antiporter; TF, Transferrin; TFRC, Transferrin receptor complexes; USP7, Ubiquitin-specific proteinase 7.

Figure 4

Ferroptosis plays an important role in the occurrence and progression of sepsis. Ferroptosis, as a specific form of regulated cell death, plays an indispensably important role in the occurrence and progression of sepsis. During the development of sepsis, the complex pathophysiological environment, including excessive inflammation, oxidative stress, and disrupted iron metabolism, creates favorable conditions for ferroptosis. The dysregulation of iron homeostasis within cells leads to an accumulation of iron ions, which act as catalysts for lipid peroxidation. Inflammatory cytokines and reactive oxygen species generated during sepsis can further disrupt the antioxidant defense system within cells, thereby exacerbating lipid peroxidation. This process of ferroptosis in turn aggravates tissue damage, impairs organ function, and promotes the continuous progression of sepsis, ultimately having a profound impact on the prognosis of patients with this severe condition. AUF1, AU-rich element RNA binding factor 1; CLP, Cecal ligation and puncture; Dex, Dexmedetomidine; DFO, Deferoxamine; DFP, Deferiprone; FAO, Fatty acid oxidation; Fe²⁺, Iron ion; Fer-1, Ferrostatin-1; GSH, Glutathione; GPX4, Glutathione peroxidase 4; LPS, Lipopolysaccharide; MCTR1, Maresin conjugates in tissue regeneration-1; MDA, Malondialdehyde; MFG-E8, Epidermal growth factor 8; NADPH, Nicotinamide adenine dinucleotide phosphate; NRF2, Nuclear factor erythroid 2-related factor 2; ROS, Reactive oxygen species; YAP1, Yes1 associated transcriptional regulator; 4-HNE, 4-hydroxynonenal.