Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 14, 2024

Iron, an essential mineral in the body, is involved numerous physiological processes, making maintenance of iron homeostasis crucial for overall health. Both overload and deficiency can cause various disorders human diseases. Ferroptosis, a form cell death dependent on iron, characterized by extensive peroxidation lipids. Unlike other kinds classical unprogrammed death, ferroptosis primarily linked to disruptions metabolism, lipid peroxidation, antioxidant system imbalance. Ferroptosis regulated through transcription, translation, post-translational modifications, which affect cellular sensitivity ferroptosis. Over past decade or so, diseases have been as part their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous cardiovascular musculoskeletal Ferroptosis-related proteins become attractive targets many major that are currently incurable, some regulators shown therapeutic effects clinical trials although further validation potential needed. Therefore, in-depth analysis its molecular mechanisms may offer additional strategies prevention treatment. In this review, we discuss significance contribution etiology development along with evidence supporting targeting approach. Importantly, evaluate recent promising interventions, providing guidance future targeted treatment therapies against

Language: Английский

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α-Ketoglutarate improves cardiac insufficiency through NAD+-SIRT1 signaling-mediated mitophagy and ferroptosis in pressure overload-induced mice

Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(1)

Published: Jan. 22, 2024

Abstract Background In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy fibrosis mice HF improved cardiac insufficiency. However, the protective mechanism of AKG remains unclear. We verified hypothesis that improves function by upregulating NAD + levels activating silent information regulator 2 homolog 1 (SIRT1) cardiomyocytes. Methods vivo, 2% was added drinking water undergoing transverse aortic constriction (TAC) surgery. Echocardiography biopsy were performed evaluate pathological changes. Myocardial metabolomics analyzed liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after vitro, expression SIRT1 or PINK1 proteins inhibited selective inhibitors siRNA cardiomyocytes stimulated angiotensin II (AngII) AKG. detected using an test kit. Mitophagy ferroptosis evaluated Western blotting, qPCR, JC-1 staining lipid peroxidation analysis. Results supplementation TAC surgery could alleviate improve mice. Metabolites malate-aspartate shuttle (MAS) increased, but TCA cycle fatty acid metabolism pathway be myocardium supplementation. Decreased protein observed AngII-treated After treatment, these changes reversed, increased mitophagy, ferroptosis, damage observed. When inhibitor siRNA, effect suppressed. Conclusion can hypertrophy, chronic insufficiency caused pressure overload. By increasing level , SIRT-PINK1 SIRT1-GPX4 signaling pathways are activated promote mitophagy inhibit cardiomyocytes, which ultimately alleviates damage.

Language: Английский

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Rationale and design of the FAIR‐HF2‐DZHK05 trial: Ferric carboxymaltose assessment of morbidity and mortality in patients with iron deficiency and chronic heart failure

European Journal of Heart Failure, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Abstract Aims While it is widely accepted that intravenous (IV) iron improves functional capacity, symptoms, and cardiovascular outcomes in patients with heart failure (HF) reduced ejection fraction (HFrEF) diagnosed deficiency (ID), three recently published outcome trials (AFFIRM‐AHF, IRONMAN HEART‐FID) of IV supplementation HF failed to demonstrate a significant benefit on their respective primary endpoints. Dosing after the initial correction baseline ID – by design or as result trial circumstances was relatively low (i.e. <500 mg/year). The objective FAIR‐HF2 evaluate treatment effect ferric carboxymaltose (FCM) compared placebo ambulatory HFrEF using higher dose during follow‐up >1000 second study create prospective evidence for fulfilling new definition HF, i.e. those transferrin saturation <20%. Methods an investigator‐initiated, multicentre, randomized, double‐blind, placebo‐controlled has recruited 1105 chronic left ventricular ≤45% concomitant ID, defined serum ferritin <100 ng/ml 100–299 Patients were consented randomized receive either FCM (treatment) saline (placebo). During estimated median over 2 years, underwent repletion maintenance phase, up 2000 mg, followed 500 mg every 4 months unless stop criteria haemoglobin >16 mg/dl >800 are met repeat visits. will hypotheses: (i) time first event death hospitalization (ii) rate total (first recurrent) hospitalizations (both analysed full population), (iii) <20% at baseline. familywise type I error across endpoint hypotheses be controlled Hochberg procedure (alpha 0.05). Conclusion efficacy improving utilizing more aggressive approach towards ensuring prevention transitional targets have been met.

Language: Английский

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Mechanisms of enhanced renal and hepatic erythropoietin synthesis by sodium–glucose cotransporter 2 inhibitors

European Heart Journal, Journal Year: 2023, Volume and Issue: 44(48), P. 5027 - 5035

Published: April 22, 2023

Abstract Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major heart failure events, an action that is statistically linked to enhanced erythropoiesis, suggesting stimulation erythropoietin and cardioprotection are related a shared mechanism. Four hypotheses have been proposed explain how these drugs increase production: (i) renal cortical reoxygenation with rejuvenation erythropoietin-producing cells; (ii) counterregulatory distal sodium reabsorption leading increased tubular workload oxygen consumption, thus, localized hypoxia; (iii) iron mobilization as stimulus hypoxia-inducible factor-2α (HIF-2α)-mediated synthesis; (iv) direct HIF-2α activation gene transcription due sirtuin-1 (SIRT1) signaling. The first two assume source interstitial fibroblast-like cells in deep cortex. However, SGLT2 do not alter regional tissue tension non-diabetic kidney, synthesis markedly impaired patients anemia chronic kidney disease, yet, produce unattenuated erythrocytic response patients. This observation raises possibility liver contributes production during inhibition. Hypoxia-inducible coexpressed only but also hepatocytes; site when maintained for prolonged periods. ability improve by derepressing hepcidin ferritin would be expected cytosolic ferrous iron, which might stimulate expression both through regulatory protein 1. Alternatively, established enhance SIRT1 mechanism drugs. In hepatic cell lines, can directly activate deacetylation, additionally, effect SIRT liver, peroxisome proliferator-activated receptor-γ coactivator-1α binds nuclear factor 4 promote erythropoietin. Since up-regulation exerts cytoprotective effects on stimulates erythropoietin, it well-positioned represent links erythropoiesis

Language: Английский

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Redefining Iron Deficiency in Patients With Chronic Heart Failure

Circulation, Journal Year: 2024, Volume and Issue: 150(2), P. 151 - 161

Published: May 11, 2024

A serum ferritin level <15 to 20 μg/L historically identified patients who had absent bone marrow iron stores, but levels are distorted by the systemic inflammatory states seen in with chronic kidney disease or heart failure. As a result, nearly 25 years ago, diagnostic threshold was increased 5- 20-fold (ie, deficiency if <100 μg/L, regardless of transferrin saturation [TSAT], 100 299 TSAT <20%). This guidance motivated not findings studies total body tissue depletion, desire encourage use supplements potentiate response erythropoiesis-stimulating agents renal anemia. However, failure, this definition does reliably identify an absolute functional iron-deficiency state, and it includes individuals TSATs (≥20%) normal range (20-100 mg/L) deficient, have excellent prognosis, do respond favorably therapy. Furthermore, may be both neprilysin sodium-glucose cotransporter 2 inhibitors, which act mobilize endogenous stores. The most evidence-based trial-tested is presence hypoferremia, as reflected <20%. These hypoferremic generally deficient on examination, after intravenous therapy, they exhibit improvement exercise tolerance capacity (when meaningfully impaired) show marked reduction 20%-30%) risk cardiovascular death failure hospitalizations. Therefore, we propose that current ferritin-driven should abandoned based hypoferremia (TSAT <20%) adopted.

Language: Английский

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Iron deficiency and supplementation in heart failure

Nature Reviews Cardiology, Journal Year: 2024, Volume and Issue: 21(7), P. 463 - 486

Published: Feb. 7, 2024

Language: Английский

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Randomized trial to assess worsening renal function by adding dapagliflozin for acute decompensated heart failure

ESC Heart Failure, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract Aims Dapagliflozin (DAPA), a sodium‐glucose co‐transporter 2 inhibitor, has been shown to reduce cardiovascular mortality among patients with chronic heart failure. We aimed evaluate the impact on worsening renal function (WRF) by adding DAPA as compared standard decongestive therapy loop diuretics alone. Methods and results enrolled 114 consecutive acute decompensated failure (ADHF) left ventricular ejection fraction (LVEF) of less than 50%. The were prospectively randomized be assigned either group who received at dose 10 mg once daily within 24 h after admission or conventional (CON group) All adjusted increasing decreasing diuretic maintain 1–2 mL/kg/h urine output. primary endpoint was incidence WRF, which defined an increase in serum creatinine ≥0.3 mg/dL from baseline. median age 77 [interquartile range (IQR): 64, 85] years, 35% female LVEF 33 [IQR: 28, 38] %. There no significant difference WRF between two groups (16.1%, n = 9 vs. 12.1%, 7, P value 0.54). total through day 7 lower CON (184 ± 79.5 214 66.5 mg, 0.03). Conclusions This prospective trial revealed addition reduced without WRF.

Language: Английский

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Anemia Management in the Cardiorenal Patient: A Nephrological Perspective

Journal of the American Heart Association, Journal Year: 2025, Volume and Issue: 14(5)

Published: March 3, 2025

Heart failure (HF) and chronic kidney disease (CKD) frequently coexist, sharing significant overlap in prevalence pathophysiological mechanisms. This coexistence, termed cardiorenal syndrome (CRS), often leads to anemia, which exacerbates both HF CKD, thereby increasing morbidity death. Managing anemia CRS is complex due conflicting guidelines the multifactorial nature of condition. Anemia influenced by factors such as inadequate erythropoietin production, iron deficiency, reduced red blood cell life span, inflammation, inhibit absorption mobilization. interplay mechanisms worsens further aggravating CKD. significantly impacts prognosis recent trials have shown that hemoglobin increases, particularly with sodium–glucose cotransporter 2 inhibitors, can improve outcomes patients Iron deficiency also prevalent CKD associated poorer exercise capacity a higher mortality rate. Guidelines for diagnosing treating differ between Furthermore, treatment controversial: While inhibitors intravenous has consistent benefits CRS, normalization erythropoiesis‐stimulating agents improves symptoms quality but not consistently demonstrated cardiovascular benefits. There are no definitive management CRS. Treatment should address HF, concurrently. A proposed algorithm includes correcting initiating considering if remains <10 g/dL. Further research needed optimize strategies

Language: Английский

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Intravenous iron and SGLT2 inhibitors in iron‐deficient patients with heart failure and reduced ejection fraction

ESC Heart Failure, Journal Year: 2024, Volume and Issue: 11(4), P. 1875 - 1879

Published: March 28, 2024

To explore the potential interaction between use of SGLT2 inhibitors and increase in haemoglobin patients randomized to intravenous iron or control group IRONMAN (Effectiveness Intravenous Iron Treatment versus Standard Care Patients with Heart Failure Deficiency) trial.

Language: Английский

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Targeting ferroptosis, a novel programmed cell death, for the potential of alcohol-related liver disease therapy

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: May 5, 2023

Ferroptosis is a new iron-dependent cell death mode, which different from the other types of programmed death, such as apoptosis, necrosis, and autophagy. characterized by process in fatal lipids lipid peroxidation accumulate cells eventually lead to death. Alcohol-related liver disease (ALD) type injury caused excessive alcohol intake. broad-spectrum category, includes fatty liver, steatohepatitis, hepatitis, cirrhosis, hepatocellular tumors. Recent studies have found that ferroptosis involved pathological development non-viral diseases. Therefore, may be an ideal target for treatment In this review article, we will elaborate molecular mechanism regulatory ferroptosis, explore key role process, summarize existing targeted drugs their feasibility disease.

Language: Английский

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