Explore the vast range of titles available.

The maintenance of iron homeostasis is essential for proper cardiac function. A growing body of evidence suggests that iron imbalance is the common denominator in many subtypes of cardiovascular disease. In the past 10 years, ferroptosis, an iron-dependent form of regulated cell death, has become increasingly recognized as an important process that mediates the pathogenesis and progression of numerous cardiovascular diseases, including atherosclerosis, drug-induced heart failure, myocardial ischaemia–reperfusion injury, sepsis-induced cardiomyopathy, arrhythmia and diabetic cardiomyopathy. Therefore, a thorough understanding of the mechanisms involved in the regulation of iron metabolism and ferroptosis in cardiomyocytes might lead to improvements in disease management. In this Review, we summarize the relationship between the metabolic and molecular pathways of iron signalling and ferroptosis in the context of cardiovascular disease. We also discuss the potential targets of ferroptosis in the treatment of cardiovascular disease and describe the current limitations and future directions of these novel treatment targets.Since the discovery of ferroptosis a decade ago, this iron-dependent form of regulated cell death has been implicated in the pathogenesis of cardiovascular disease. In this Review, Fudi Wang and colleagues discuss the link between the metabolic pathways of iron signalling and ferroptosis in the context of the cardiovascular system and describe the potential of ferroptosis inhibitors in the treatment of cardiovascular disease.

As an essential micronutrient, copper is required for a wide range of physiological processes in virtually all cell types. Because the accumulation of intracellular copper can induce oxidative stress and perturbing cellular function, copper homeostasis is tightly regulated. Recent studies identified a novel copper-dependent form of cell death called cuproptosis, which is distinct from all other known pathways underlying cell death. Cuproptosis occurs via copper binding to lipoylated enzymes in the tricarboxylic acid (TCA) cycle, which leads to subsequent protein aggregation, proteotoxic stress, and ultimately cell death. Here, we summarize our current knowledge regarding copper metabolism, copper-related disease, the characteristics of cuproptosis, and the mechanisms that regulate cuproptosis. In addition, we discuss the implications of cuproptosis in the pathogenesis of various disease conditions, including Wilson’s disease, neurodegenerative diseases, and cancer, and we discuss the therapeutic potential of targeting cuproptosis.

Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, diseases involving tissue and/or organ injury, and inflammatory and infectious diseases. Although the precise regulatory networks that underlie ferroptosis are largely unknown, particularly with respect to the initiation and progression of various diseases, ferroptosis is recognized as a bona fide target for the further development of treatment and prevention strategies. Over the past decade, considerable progress has been made in developing pharmacological agonists and antagonists for the treatment of these ferroptosis-related conditions. Here, we provide a detailed overview of our current knowledge regarding ferroptosis, its pathological roles, and its regulation during disease progression. Focusing on the use of chemical tools that target ferroptosis in preclinical studies, we also summarize recent advances in targeting ferroptosis across the growing spectrum of ferroptosis-associated pathogenic conditions. Finally, we discuss new challenges and opportunities for targeting ferroptosis as a potential strategy for treating ferroptosis-related diseases.

Ferroptosis is defined as an iron-dependent regulated form of cell death driven by lipid peroxidation. In the past decade, it has been implicated in the pathogenesis of various diseases that together involve almost every organ of the body, including various cancers, neurodegenerative diseases, cardiovascular diseases, lung diseases, liver diseases, kidney diseases, endocrine metabolic diseases, iron-overload-related diseases, orthopedic diseases and autoimmune diseases. Understanding the underlying molecular mechanisms of ferroptosis and its regulatory pathways could provide additional strategies for the management of these disease conditions. Indeed, there are an expanding number of studies suggesting that ferroptosis serves as a bona-fide target for the prevention and treatment of these diseases in relevant pre-clinical models. In this review, we summarize the progress in the research into ferroptosis and its regulatory mechanisms in human disease, while providing evidence in support of ferroptosis as a target for the treatment of these diseases. We also discuss our perspectives on the future directions in the targeting of ferroptosis in human disease.

Ferroptosis, a newly defined mode of regulated cell death caused by unbalanced lipid redox metabolism, is implicated in various tissue injuries and tumorigenesis. However, the role of ferroptosis in stem cells has not yet been investigated. Glutathione peroxidase 4 (GPX4) is a critical suppressor of lipid peroxidation and ferroptosis. Here, we study the function of GPX4 and ferroptosis in hematopoietic stem and progenitor cells (HSPCs) in mice with Gpx4 deficiency in the hematopoietic system. We find that Gpx4 deletion solely in the hematopoietic system has no significant effect on the number and function of HSPCs in mice. Notably, hematopoietic stem cells (HSCs) and hematopoietic progenitor cells lacking Gpx4 accumulated lipid peroxidation and underwent ferroptosis in vitro. α-Tocopherol, the main component of vitamin E, was shown to rescue the Gpx 4-deficient HSPCs from ferroptosis in vitro. When Gpx4 knockout mice were fed a vitamin E-depleted diet, a reduced number of HSPCs and impaired function of HSCs were found. Furthermore, increased levels of lipid peroxidation and cell death indicated that HSPCs undergo ferroptosis. Collectively, we demonstrate that GPX4 and vitamin E cooperatively maintain lipid redox balance and prevent ferroptosis in HSPCs.

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

Abstract Context Iron overload is a known risk factor for type 2 diabetes (T2D); however, iron overload and iron deficiency have both been associated with metabolic disorders in observational studies. Objective Using mendelian randomization (MR), we assessed how genetically predicted systemic iron status affected T2D risk. Methods A 2-sample MR analysis was used to obtain a causal estimate. We selected genetic variants strongly associated (P < 5 × 10−8) with 4 biomarkers of systemic iron status from a study involving 48 972 individuals performed by the Genetics of Iron Status consortium and applied these biomarkers to the T2D case-control study (74 124 cases and 824 006 controls) performed by the Diabetes Genetics Replication and Meta-analysis consortium. The simple median, weighted median, MR-Egger, MR analysis using mixture-model, weighted allele scores, and MR based on a Bayesian model averaging approaches were used for the sensitivity analysis. Results Genetically instrumented serum iron (odds ratio [OR]: 1.07; 95% CI, 1.02-1.12), ferritin (OR: 1.19; 95% CI, 1.08-1.32), and transferrin saturation (OR: 1.06; 95% CI, 1.02-1.09) were positively associated with T2D. In contrast, genetically instrumented transferrin, a marker of reduced iron status, was inversely associated with T2D (OR: 0.91; 95% CI, 0.87-0.96). Conclusion Genetic evidence supports a causal link between increased systemic iron status and increased T2D risk. Further studies involving various ethnic backgrounds based on individual-level data and studies regarding the underlying mechanism are warranted for reducing the risk of T2D.

Heart disease is the leading cause of death worldwide. A key pathogenic factor in the development of lethal heart failure is loss of terminally differentiated cardiomyocytes. However, mechanisms of cardiomyocyte death remain unclear. Here, we discovered and demonstrated that ferroptosis, a programmed iron-dependent cell death, as a mechanism in murine models of doxorubicin (DOX)- and ischemia/reperfusion (I/R)-induced cardiomyopathy. In canonical apoptosis and/or necroptosis-defective Ripk3−/−, Mlkl−/−, or Fadd−/−Mlkl−/− mice, DOX-treated cardiomyocytes showed features of typical ferroptotic cell death. Consistently, compared with dexrazoxane, the only FDA-approved drug for treating DOX-induced cardiotoxicity, inhibition of ferroptosis by ferrostatin-1 significantly reduced DOX cardiomyopathy. RNA-sequencing results revealed that heme oxygenase-1 (Hmox1) was significantly up-regulated in DOX-treated murine hearts. Administering DOX to mice induced cardiomyopathy with a rapid, systemic accumulation of nonheme iron via heme degradation by Nrf2-mediated upregulation of Hmox1, which effect was abolished in Nrf2-deficent mice. Conversely, zinc protoporphyrin IX, an Hmox1 antagonist, protected the DOX-treated mice, suggesting free iron released on heme degradation is necessary and sufficient to induce cardiac injury. Given that ferroptosis is driven by damage to lipid membranes, we further investigated and found that excess free iron accumulated inmitochondria and caused lipid peroxidation on its membrane. Mitochondria-targeted antioxidant MitoTEMPO significantly rescued DOX cardiomyopathy, supporting oxidative damage of mitochondria as a major mechanism in ferroptosis-induced heart damage. Importantly, ferrostatin-1 and iron chelation also ameliorated heart failure induced by both acute and chronic I/R in mice. These findings highlight that targeting ferroptosis serves as a cardioprotective strategy for cardiomyopathy prevention.

The recent outbreak of COVID-19 has been rapidly spreading on a global scale. To date, there is no specific vaccine against the causative virus, SARS-CoV-2, nor is there an effective medicine for treating COVID-19, thus raising concerns with respect to the effect of risk factors such as clinical course and pathophysiological parameters on disease severity and outcome in patients with COVID-19. By extracting and analyzing all available published clinical data, we identified several major clinical characteristics associated with increased disease severity and mortality among patients with COVID-19. Specifically, preexisting chronic conditions such as hypertension, cardiovascular disease, chronic kidney disease, and diabetes are strongly associated with an increased risk of developing severe COVID-19; surprisingly, however, we found no correlation between chronic liver disease and increased disease severity. In addition, we found that both acute cardiac injury and acute kidney injury are highly correlated with an increased risk of COVID-19-related mortality. Given the high risk of comorbidity and the high mortality rate associated with tissue damage, organ function should be monitored closely in patients diagnosed with COVID-19, and this approach should be included when establishing new guidelines for managing these high-risk patients. Moreover, additional clinical data are needed in order to determine whether a supportive therapy can help mitigate the development of severe, potentially fatal complications, and further studies are needed to identify the pathophysiology and the mechanism underlying this novel coronavirus-associated infectious disease. Taken together, these findings provide new insights regarding clinical strategies for improving the management and outcome of patients with COVID-19.