Ferroptosis in sepsis: The mechanism, the role and the therapeutic potential

Abstract

Sepsis is a common critical illness in the Intensive care unit(ICU) and its management and treatment has always been a major challenge in critical care medicine. The dysregulated host response to infection, causing systemic multi-organ and multi-system damage is the main pathogenesis. Notably, intense stress during sepsis can lead to metabolic disturbances of ions, lipids and energy in the organism. Ferroptosis is an iron-dependent, non-apoptotic cell death distinguished by a disruption of iron metabolism and iron-dependent accumulation of lipid peroxides. Mounting researches have established that ferroptosis has an essential part in anti-inflammatory and sepsis, and drugs targeting ferroptosis-related molecules, such as ferroptosis inhibitors, are gradually proving their effectiveness in sepsis. This paper summarizes and reviews the pathogenesis of ferroptosis, its regulatory network, and its vital involvement in the initiation of sepsis and related organ damage, and finally discusses the possible target drugs provided by the above mechanisms, describes the dilemmas as well as the outlook, in the hope of finding more links between ferroptosis and sepsis and providing new perspectives for the future treatment of sepsis.

Keywords: Nrf2; P53; autophagy; ferroptosis; mTOR; organ damage; sepsis; treatment.

Figure 1

The occurrence mechanism of ferroptosis. The pathways by which ferroptosis is caused are reviewed, including disorders of iron metabolism, lipid peroxidation, and breakdown of the antioxidant system. Excessive accumulation of intracellular iron induces lipid peroxidation through the Fenton reaction, the disruption of the antioxidant system leads to the accumulation of lipid peroxidation products and the above processes ultimately lead to ferroptosis. Abbreviations: Tf, transferrin; TfR1, transferrin receptor 1; Fe2+, ferrous iron; Fe3+, ferric iron; FPN, ferroportin; FT, ferritin; DMT1, divalent metal transporter 1; HO•, hydroxyl radicals; LOXs, lipoxygenases; PL, phospholipid; PLOOH, phospholipid hydroperoxide; PUFA, polyunsaturated fatty acid; MDA, Malonaldehyde; 4-HNE, 4 hydroxynonenal; GPX4, glutathione peroxidase 4; GSH, glutathione; GS-SG, oxidized glutathione; FSP1, ferroptosis suppressor protein 1; CoQ10, coenzyme Q10; DHODH, dihydroor otate dehydrogenase; DHO, dihydroorotate; BH4, Tetrahydrobiopterin; GCH, GTP cyclic hydrolase;.

Figure 2

Regulatory pathways of ferroptosis: Nrf2 and mTOR. Normally, Nrf2 is bound by keap1 and then degraded. When the body is under oxidative stress, it translocates into the nucleus and regulates transcription. Nrf2 moderates ferroptosis by acting on iron metabolism and antioxidant systems. Nrf2 can promote the expression of ferritin and FPN, HRG1 and FECH to control the recycling, storage, and utilization of iron. Additionally, the expression of SLC7A11, GPX4, HO-1, and GCH1 facilitated by Nrf2 enhances the effect of the antioxidant system. The impact of mTOR on ferroptosis is two-fold. For one thing, mTOR reduces intracellular iron concentrations by inhibiting TF/TfR transcription and promoting TfR degradation, and enhances the synthesis of monounsaturated fatty acids, two pathways that inhibit the onset of ferroptosis. In contrast, mTOR facilitates ferroptosis by repressing the Xc system and reducing GSH synthesis. mTOR also has a dual effect on GPX4. Abbreviations: Nrf2, nuclear factor erythroid 2-related factor 2; FPN, ferroportin; HRG1, heme responsive gene-1; FECH, ferrochelatase; SLC7A11, solute carrier family 7 member 11; GPX4, glutathione peroxidase 4; HO-1, heme oxygenase-1; GCH1, GTP Cyclohydrolase 1; Tf, transferrin; TfR, transferrin receptor.

Figure 3

Regulatory pathways of ferroptosis: autophagy and P53.Selective autophagy promotes ferroptosis by facilitating thedegradation of key molecules of it and related organellesautophagy. NCOA4-promoted ferritin degradation; RAB7Amediatedlipid droplets degradation; haperone-mediatedautophagy (CMA) –mediated GPX4 degradation; sequestosome-1(SQSTM1/P62)-mediated Aryl hydrocarbon receptor nucleartranslocator-like protein 1(ARNTL) degradation; overexpressionof cathepsin B significantly promotes ferroptosis via theactivation of lysosomal cell death; PINK1 and PRKN/PARK2regulated mitophagy. The dual role of P53 in ferroptosis isreflected in its regulation of iron metabolism, the GSH-GPX4axis, and lipid metabolism. P53 increases intracellular ironconcentration via SLC25A28 and TfR, thereby promotingferroptosis. P53 inhibits the activity of the Xc system and reducesGSH synthesis, but also slows GSH depletion via P21. In terms oflipid peroxidation, P53 prevents lipid peroxidation through DPP4and Parkin, but also promotes it by manipulating SLC7A11 andSAT1. Abbreviations: NCOA4, nuclear receptor coactivator 4;RAB7A, RAB7A, member RAS oncogene family; CMA, chaperonemediatedautophagy; SQSTM1, sequestosome 1; ARNTL, arylhydrocarbon receptor nuclear translocator like; PINK1, PTENinducedkinase 1; PRKN/PARK2, Parkin RBR E3 ubiquitin proteinligase (PRKN/PARK2); GPX4, glutathione peroxidase 4; GSH,glutathione; DPP4, dipeptidyl peptidase 4; SAT1, spermidine/spermine N1-acetyltransferase 1; SLC7A11, solute carrier family 7member 11; TP53, tumor protein P53.