Epstein-Barr Virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human T-cell leukemia virus type 1 (HTLV-1) are key infectious agents linked to the development of various hematological malignancies, including Hodgkin's lymphoma, non-Hodgkin's lymphoma, and adult T-cell leukemia/lymphoma. This review highlights the critical knowledge gaps in understanding the role of ferroptosis, a novel form of cell death, in virus-related tumors. We focus on how ferroptosis influences the host cell response to these viral infections, revealing groundbreaking mechanisms by which the three viruses differentially regulate core pathways of ferroptosis, such as iron homeostasis, lipid peroxidation, and antioxidant systems, thereby promoting malignant transformation of host cells. Additionally, we explore the potential of antiviral drugs and ferroptosis modulators in the treatment of virus-associated hematological malignancies.

Cancer remains a significant barrier to human longevity and a leading cause of mortality worldwide. Despite advancements in cancer therapies, challenges such as cellular toxicity and drug resistance to chemotherapy persist. Regulated cell death (RCD), once regarded as a passive process, is now recognized as a programmed mechanism with distinct biochemical and morphological characteristics, thereby presenting new therapeutic opportunities. Ferroptosis, a novel form of RCD characterized by iron-dependent lipid peroxidation and unique mitochondrial damage, differs from apoptosis, autophagy, and necroptosis. It is driven by reactive oxygen species (ROS)-induced lipid peroxidation and is implicated in tumorigenesis, anti-tumor immunity, and resistance, particularly in tumors undergoing epithelial-mesenchymal transition. Moreover, ferroptosis is associated with ischemic organ damage, degenerative diseases, and aging, regulated by various cellular metabolic processes, including redox balance, iron metabolism, and amino acid, lipid, and glucose metabolism. This review focuses on the role of epigenetic factors in tumor ferroptosis, exploring their mechanisms and potential applications in cancer therapy. It synthesizes current knowledge to provide a comprehensive understanding of epigenetic regulation in tumor cell ferroptosis, offering insights for future research and clinical applications.

The most prevalent endocrine disorder affecting women is PCOS. Programmed death of ovarian cells has yet to be elucidated. Ferroptosis is a kind of iron-dependent necrosis featured by significantly Fe+2-dependent lipid peroxidation. The ongoing study aimed to reinforce fertility by combining therapy with AgNPs and (Zileuton) in PCOS rats' model.

The study included 75 adult female rats divided into 5 groups; control, PCOS, PCOS treated with AgNPs, PCOS treated with Zileuton, and PCOS group treated with AgNPs and Zileuton. The study investigated the anti-ferroptotic, anti-inflammatory, antioxidant, antiapoptotic, histopathological and immunohistochemical examinations of COX-2 and VEGF.

The combination of AgNPs and Zileuton showed significant reduction of inflammatory mediators (IL-6, TNF-α, NFk-B) compared with diseased group (P-value < 0.05), regression of ferroptosis marks (Panx1 and TLR4 expression, Fe+2 levels) compared with diseased group (P-value < 0.05), depression of apoptotic marker caspase 3 level compared with diseased animals (P-value < 0.05), depression of MDA level, elevation of HO-1, GPx4 activity, and reduction of Cox2 and VEGF as compared with the diseased, AgNPs or zileuton-treated groups (P-value < 0.05).

The study showed that the combination of AgNPs and zileuton guards against, inflammation, apoptosis, and ferroptosis in PCO.

Regulated cell death is a form of cell death that is actively controlled by biomolecules. Several studies have shown that regulated cell death plays a key role after spinal cord injury. Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords. Autophagy, a complex form of cell death that is interconnected with various regulated cell death mechanisms, has garnered significant attention in the study of spinal cord injury. This injury triggers not only cell death but also cellular survival responses. Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis, ferroptosis, and autophagy. Therefore, this review aims to comprehensively examine the mechanisms underlying regulated cell deaths, the signaling pathways that modulate these mechanisms, and the potential therapeutic targets for spinal cord injury. Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury. Moreover, a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantial nigra. Mitochondrial dysfunction and mitochondrial oxidative stress are central to the pathogenesis of PD, with recent evidence highlighting the role of ferroptosis - a type of regulated cell death dependent on iron metabolism and lipid peroxidation. Mitochondria, the central organelles for cellular energy metabolism, play a pivotal role in PD pathogenesis through the production of Reactive oxygen species (ROS) and the disruption of iron homeostasis. This review explores the intricate interplay between mitochondrial dysfunction and ferroptosis in PD, focusing on key processes such as impaired electron transport chain function, tricarboxylic acid (TCA) cycle dysregulation, disruption of iron metabolism, and altered lipid peroxidation. We discuss key pathways, including the role of glutathione (GSH), mitochondrial ferritin, and the regulation of the mitochondrial labile iron pool (mLIP), which collectively influence the susceptibility of neurons to ferroptosis. Furthermore, this review emphasizes the importance of mitochondrial quality control mechanisms, such as mitophagy and mitochondrial biogenesis, in mitigating ferroptosis-induced neuronal death. Understanding these mechanisms linking the interplay between mitochondrial dysfunction and ferroptosis may pave the way for novel therapeutic approaches aimed at preserving mitochondrial integrity and preventing neuronal loss in PD.

Sepsis-induced cardiac dysfunction, usually termed sepsis-induced cardiomyopathy or septic cardiomyopathy(SCM), is developed in approximately 70 % of the patients with sepsis, making it is a major concern for sepsis patients. However, the pathogenesis of SCM remain incompletely understood. Ferroptosis, a newly identified mechanism of regulated cell death, characterized by a decline in antioxidant capacity, iron accumulation, and lipid peroxidation(LPO), is involved in sepsis and SCM. Moreover, ferroptosis inhibitors confer a novel therapeutic regimen in SCM. In this Review, we first summarizes the core mechanism of ferroptosis, with an emphasis on how best to interpret ferroptosis leads to the genesis of SCM. We then highlights our focus on the emerging different types of therapeutic ferroptosis inhibitors and summarizes their pharmacological beneficial effect to treat SCM. This review highlights a novel potential therapeutic strategy for SCM by pharmacologically inhibiting ferroptosis.

Ultraviolet B (UVB) irradiation induces cataract pathogenesis, and Glutaredoxin 2 (Grx2) deficiency causes the early onset of UVB-induced cataracts. Several researchers have shown that, apart from apoptosis and pyroptosis, UVB irradiation also can induce cell ferroptosis. We explored the role of ferroptosis caused by UVB irradiation in human lens epithelial cells (HLECs) and clarified how Grx2 protects against UVB-induced cataracts.

HLE-B3 cells and mice lenses were treated with DMSO or ferroptosis inhibitors after various doses of UVB irradiation. Cell morphology and ultrastructure were observed by optical microscope and transmission electron microscopy. Lens opacity was observed ex vivo using an optical microscope and in vivo using a slit lamp. The lipid peroxidation level was measured by C11-BODIPY probe and 4-HNE (the lipid peroxidation marker) protein expression. Cell viability was determined using the CCK-8 kit and propodium iodide (PI) immunofluorescence. Grx2 KO and KI mice, Grx2 silencing and Grx2 overexpression in HLE-B3 cell lines were used for in vivo and in vitro experiments respectively.

UVB-caused HLE-B3 cells death, lens opacity and lipid peroxidation could be mitigated by ferroptosis inhibitors. Grx2 KO mice accelerate the appearance of lens opacity induced by UVB. Meanwhile, Grx2 silencing enhanced HLECs lipid peroxidation susceptibility, downregulated the GSH level, shrunk mitochondria, and reduced the number of cristae. Grx2 overexpression had opposite effects.

Ferroptosis appears involved in UVB-induced HLECs damage. Inhibiting ferroptosis prevented UVB-induced cataracts. Grx2 strengthens resistance to ferroptosis induced by UVB irradiation through maintaining HLEC cellular GSH/GSSG homeostasis.

Inhibiting ferroptosis has been proposed to rescue myocardial cell death in Doxorubicin (DOX)-induced cardiotoxicity (DIC). Here, we aimed to investigate whether luteolin-7-O-glucuronide (LOG) alleviates DIC via ferroptosis suppression in zebrafish and H9C2 cardiomyocytes, as well as the potential mechanism. We found that LOG improved zebrafish cardiac function and mitigated the upregulation of CK-MB, cTnT, nppa, and nppb caused by DOX. Moreover, LOG suppressed the high levels of ROS, GSSG, and MDA in response to DOX and increased GSH activity and gpx4 levels in zebrafish. Additionally, LOG increased cell viability and the GSH/GSSG ratio, reduced oxidative damage and the accumulation of ferrous ions, and maintained mitochondrial function in H9C2 cells. Mechanistically, LOG improved the abnormal expression of key genes in the PPAR signaling pathway and ferroptosis induced by DOX. In conclusion, our study emphasized that LOG attenuates DIC by mitigating oxidative stress-triggered lipid peroxidation related to the inhibition of PPAR-mediated ferroptosis.

The discovery of ferroptosis has brought a revolutionary breakthrough in heart failure treatment, and natural products, as a significant source of drug discovery, are gradually demonstrating their extraordinary potential in regulating ferroptosis and alleviating heart failure symptoms. In addition to chemically synthesized small molecule compounds, natural products have attracted attention as an important source for discovering compounds that target ferroptosis in treating heart failure.

Systematically summarize and analyze the research progress on improving heart failure through natural products' modulation of the ferroptosis pathway.

By comprehensively searching authoritative databases like PubMed, Web of Science, and China National Knowledge Infrastructure with keywords such as "heart failure", "cardiovascular disease", "heart disease", "ferroptosis", "natural products", "active compounds", "traditional Chinese medicine formulas", "traditional Chinese medicine", and "acupuncture", we aim to systematically review the mechanism of ferroptosis and its link with heart failure. We also want to explore natural small-molecule compounds, traditional Chinese medicine formulas, and acupuncture therapies that can inhibit ferroptosis to improve heart failure.

In this review, we not only trace the evolution of the concept of ferroptosis and clearly distinguish it from other forms of cell death but also establish a comprehensive theoretical framework encompassing core mechanisms such as iron overload and system xc-/GSH/GPX4 imbalance, along with multiple auxiliary pathways. On this basis, we innovatively link ferroptosis with various types of heart failure, covering classic heart failure types and extending our research to pre-heart failure conditions such as arrhythmia and aortic aneurysm, providing new insights for early intervention in heart failure. Importantly, this article systematically integrates multiple strategies of natural products for interfering with ferroptosis, ranging from monomeric compounds and bioactive components to crude extracts and further to traditional Chinese medicine formulae. In addition, non-pharmacological means such as acupuncture are also included.

This study fills the gap in the systematic description of the relationship between ferroptosis and heart failure and the therapeutic strategies of natural products, aiming to provide patients with more diverse treatment options and promote the development of the heart failure treatment field.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, represents a unique vulnerability in cancer cells. However, current ferroptosis-inducing therapies face clinical limitations due to poor cancer cell specificity, systemic toxicity, and off-target effects. Therefore, a deeper understanding of molecular regulators of ferroptosis sensitivity is critical for developing targeted therapies. The metabolic plasticity of cancer cells determines their sensitivity to ferroptosis. While mitochondrial dysfunction contributes to metabolic reprogramming in cancer, its role in modulating ferroptosis remains poorly characterized. Previously, studies have identified that mitochondrial genome also encodes several non-coding RNAs. We identified 13 novel mitochondrial genome-encoded miRNAs (mitomiRs) that are aberrantly overexpressed in triple-negative breast cancer (TNBC) cell lines and patient tumors. We observed higher levels of mitomiRs in basal-like triple-negative breast cancer (TNBC) cells compared to mesenchymal stem-like TNBC cells. Strikingly, 11 of these mitomiRs directly target the 3'UTR of ZEB1, a master regulator of epithelial-to-mesenchymal transition (EMT). Using mitomiR-3 mimic, inhibitor and sponges, we demonstrated its role as a key regulator of ZEB1 expression in TNBC cells. Inhibition of mitomiR-3 via sponge construct in basal-like TNBC, MDA-MB-468 cells, promoted ZEB1 upregulation and induced a mesenchymal phenotype. Further, mitomiR-3 inhibition in TNBC cells contributed to reduced cancer cell proliferation, migration, and invasion. Mechanistically, mitomiR-3 inhibition in TNBC cells promote metabolic reprogramming toward pro-ferroptotic pathways, including iron accumulation, increased polyunsaturated fatty acid (PUFA) metabolites, and lipid peroxidation, contributing to ferroptotic cell death via ZEB1-mediated downregulation of GPX4, a critical ferroptosis defense enzyme. We observed that mitomiR-3 inhibition significantly suppressed tumor growth in vivo. Our identified mitomiR-3 has low expression in normal breast cells, minimizing potential off-target toxicity, making them a promising target for pro-ferroptotic cancer therapy. Our study reveals a novel link between mitochondrial miRNAs and ferroptosis sensitivity in TNBC paving a way for miRNA-based therapeutics.

Pancreatic β-cell damage, a key pathology in Type 2 Diabetes Mellitus (T2DM), may be mitigated by inhibiting ferroptosis. Plantamajoside (PMS) shows promise in alleviating cellular damage and improving T2DM outcomes, though its mechanisms remain unclear. This study investigated PMS's role in suppressing ferroptosis in pancreatic β-cells via the cysteine/glutamate transporter (xCT)/ glutathione peroxidase 4 (GPX4) pathway. In our in vivo experiments, PMS was administered to T2DM mice via gavage, and its effects on tissue damage, ferroptosis, and xCT/GPX4 pathway modulation were assessed. Furthermore, in vitro experiments employed high glucose (HG) and palmitic acid (PA) conditions, to induce damage in pancreatic β-cells. We investigated the beneficial impacts of PMS on pancreatic β-cell damage, its modulation of ferroptosis, and its influence on the xCT/GPX4 pathway. To compare the capacity of PMS to inhibit ferroptosis, we utilized the ferroptosis inhibitor ferrostatin-1 (Fer-1) as a positive control, while the GPX4 inhibitor RSL-3 validated PMS's mechanism through the xCT/GPX4 axis. Our findings revealed that PMS effectively mitigated pancreatic tissue damage in T2DM mice, reduced ferroptosis, and enhanced the expression of factors associated with the xCT/GPX4 pathway. Moreover, PMS alleviated HG and PA-induced damage in pancreatic β-cells, suppressed ferroptosis, and upregulated factors linked to the xCT/GPX4 pathway. Similar to the ferroptosis inhibitor Fer-1, PMS exhibited comparable effects. Conversely, RSL-3 attenuated the protective effects of PMS on pancreatic β-cell damage, its inhibition of ferroptosis, and its activation of the xCT/GPX4 pathway. PMS exhibited the capacity to diminish damage to pancreatic islet β-cells induced by T2DM, both in vivo and in vitro. This favorable outcome may stem from the alleviation of lipid peroxidation and reduction of ferroptosis. Moreover, this regulatory mechanism was accomplished through the enhancement of the xCT/GPX4 axis.

Ferroptosis is a form of regulated cell death characterized by iron accumulation and increased lipid peroxidation, primarily counteracted by a range of antioxidant molecules, including glutathione (GSH), glutathione peroxidase 4 (GPX4), ubiquinone, tetrahydrofolate, and nuclear respiratory factor 2. Furthermore, the process of ferroptosis is intricately influenced by the opposing actions of the p53 tumor suppressor gene and activated transcription factors 3 and 4, which can either facilitate or hinder ferroptotic cell death depending on the cellular context. This form of cell death is significantly associated with various pancreatic disorders, including both acute and chronic pancreatitis, as well as diabetes mellitus. In this review, we thoroughly investigate the mechanisms underlying ferroptosis, focusing on iron overload, lipid peroxidation, and the regulatory molecules involved in ferroptosis modulation (notably the system xc-/GSH/GPX4 axis), along with the relevant signaling pathways. We also examine the role of ferroptosis in non-neoplastic pancreatic diseases such as pancreatitis and diabetes mellitus while identifying novel therapeutic agents that target ferroptosis, potentially paving the way for innovative treatment strategies for pancreatic conditions.

Myelination is a critical neurodevelopmental process where nerve fibers are encased with the lipid-rich, insulating substance known as myelin. It is essential for proper function of the nervous system, as myelin enhances the fidelity and speed of nerve conduction, while also providing a protective barrier. The early postnatal period represents the most rapid phase of myelination, where numbers of mature oligodendrocytes peak. Oligodendrocyte maturation is an energetically demanding process that involves increased iron uptake, heightened metabolism, and elevated production of antioxidants. It is critically dependent upon thyroid hormone signaling and increased synthesis of plasmenyl-phosphatidylethanolamine (PE; aka plasmalogen), a subclass of phospholipids that is particularly abundant in the brain. Plasmenyl-PE is characterized by a vinyl-ether bond that preferentially reacts with oxidants, thereby protecting against lipid peroxidation. Notably, thyroid hormone metabolism and plasmenyl-PE synthesis both require selenoproteins, a clade of proteins containing the 21st amino acid, selenocysteine. Selenoproteins also constitute key regulators of redox tone, with glutathione peroxidase 4 recognized as the master regulator of ferroptosis, a non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. This review aims to illuminate the delicate balance between iron homeostasis, lipid metabolism, thyroid hormone signaling, and selenoprotein synthesis in oligodendrocytes. This interconnected relationship is of paramount importance for neurodevelopment, as mutations in many genes mediating these processes converge on a phenotype characterized by hypomyelination, cognitive impairment, neurodegeneration, and motor deficits.

Acute kidney injury (AKI), a clinical syndrome marked by high morbidity and mortality, remains a significant challenge due to the lack of effective therapeutic options. The accumulation of Fe2+ and reactive oxygen species (ROS) in injured renal cells, which triggers ferroptosis, play a key driver in the pathogenesis of AKI. In this study, tetrahydroberberine (THB), a natural product, was identified as a ferroptosis inhibitor that targeted the voltage-dependent anion channel (VDAC). Through structural optimization, a series of THB derivatives were developed, among which 34a exhibited about 100-fold enhanced ferroptosis inhibitory activity. Moreover, 34a significantly reduced ROS, Fe2+ and restored glutathione (GSH) below 20 nM. In vivo experiments confirmed that 34a effectively alleviated folic acid-induced AKI, accompanied by a reduction in key kidney injury markers. These results highlight the potential of 12-amino THB derivatives as novel ferroptosis inhibitors and provide promising therapeutic strategies for AKI treatment.

Glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) are two mitochondrial cellular defense systems that operate in parallel to protect against ferroptosis. Simultaneously deactivating both proteins can initiate lipid peroxidation, leading to ferroptosis and subsequent cell death. In this study, we developed a transferrin-modified liposomes (TDPL) doped with unsaturated fatty acid docosahexaenoic acid (DHA) as a lipid peroxidation inducer and encapsulated piperine (PIP) to realize effective anticancer therapy. Specifically, transferrin serves a dual role in this system, acting as both a ligand targeting transferrin receptors and a Fe3+ ionophore. Triggered by the low pH in the lysosome, Fe3+ ions bound to transferrin are released and reduce to Fe2+, which can subsequently catalyze the peroxidation of unsaturated fatty acid. Meanwhile, DHA incorporated into the lipid bilayer of the liposome, can fuse with the cell membrane and deactivate GPX4 and thus inducing lipid peroxidation. Furthermore, PIP functions as a potent DHODH inhibitor. Such combination prevents the detoxification of lipid hydroperoxides by GPX4 and the suppression of lipid peroxyl radical production by DHODH. Collectively, this straightforward system promotes antitumor efficacy of unsaturated fatty acid DHA and drug molecule PIP by inhibiting ferroptosis protection mechanisms to induce lipid peroxidation.

Diabetic cardiomyopathy (DCM) is one of the cardiovascular complications of diabetes mellitus, which is different from myocardial damage caused by coronary ischemia, hypertension, and valvular disease. DCM lacks distinct clinical manifestations in its early stages, and current therapeutic approaches primarily focus on symptomatic management. Emerging evidence indicates that even with optimized glycemic regulation, the pathophysiological progression of DCM remains unmitigated. Exploring the pathogenic mechanism of DCM is the focus and hotspot of current research. Ferroptosis, an iron-dependent form of regulatory cell death, is crucial in DCM myocardial damage. Dysfunctional antioxidant defense system, increased oxidative stress, and elevated reactive oxygen species are the key mechanisms of ferroptosis in DCM. Thus, this review innovatively takes antioxidant proteins as the entry point, and for the first time systematically summarizes the molecular mechanism of antioxidant proteins to improve DCM by regulating the ferroptosis pathway, and summarizes the therapeutic strategy of medications to enhance ferroptosis in DCM by targeting the expression of antioxidant proteins, to explore the potential targets to improve ferroptosis in DCM, to provide a new perspective for the study of delaying the progression of DCM.

Ferroptosis is a form of regulated cell death (RCD) caused by the accumulation of intracellular iron and lipids and is involved in many pathological processes, including neurodegenerative and cardiovascular diseases, and cancer. Long non-coding RNAs (lncRNAs), RNA molecules exceeding 200 nt in length that do not possess protein coding function can interfere with ferroptosis by binding ferroptosis-related miRNAs or proteins. Recently, ferroptosis-related lncRNAs (FRlncRNAs) have been identified in cancer and non-malignant disease models, including inprediction of drug resistance, intra-tumoral immune infiltration, metabolic reprogramming and mutation landscape. Here, we review FRlncRNAs in cancer and non-malignant diseases, from prognosis to treatment.

Autoimmune diseases are a class of chronic disorders characterized by the aberrant activation of the immune system, where macrophages play a central role in regulating immune responses during disease onset and progression. Ferroptosis, a form of iron-dependent programmed cell death, has recently attracted significant interest due to its involvement in various pathological conditions. In macrophages, ferroptosis not only compromises cell viability but also disrupts immune homeostasis by promoting pro-inflammatory responses and suppressing anti-inflammatory pathways, thereby intensifying inflammation and exacerbating disease severity. While substantial progress has been made in elucidating macrophage ferroptosis in atherosclerosis and oncology, its precise mechanistic role in autoimmune diseases remains largely unexplored. This review systematically summarizes the molecular mechanisms of macrophage ferroptosis and its regulatory effects on immune homeostasis, with particular emphasis on its role in autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), and systemic sclerosis (SSc). Furthermore, we discuss potential therapeutic targets related to macrophage ferroptosis in these conditions. By integrating current knowledge, this review aims to provide a theoretical framework and novel perspectives for developing innovative therapeutic strategies targeting autoimmune diseases.

Ferroptosis is a form of regulated cell death characterized by the accumulation of lipid peroxides. The enzyme 15-lipoxygenase-1 (15-LOX-1) plays a key role in catalyzing the formation of lipid peroxides. Therefore, inhibition of 15-LOX-1 enzyme activity holds promise to decrease the levels of lipid peroxidation. In this study, a novel potent 15-LOX-1 inhibitor, 5i, was developed and structure-activity relationships were explored. In vitro, this inhibitor inhibited lipid peroxidation and protected cells from RSL3-induced cell death. Thus, we report a potent 15-LOX-1 inhibitor, which can be used as a tool to investigate the role of 15-LOX-1.

Ferroptosis is a type of iron‑dependent cell death characterized by excessive lipid peroxidation and may serve as a potential therapeutic target in cancer treatment. While the mechanisms governing ferroptosis continue to be explored and elucidated, an increasing body of research highlights the significant impact of epigenetic modifications on the sensitivity of cancer cells to ferroptosis. Epigenetic processes, such as DNA methylation, histone modifications and non‑coding RNAs, have been identified as key regulators that modulate the expression of ferroptosis‑related genes. These alterations can either enhance or inhibit the sensitivity of gastrointestinal cancer (GIC) cells to ferroptosis, thereby affecting the fate of GICs. Drugs that target epigenetic markers for advanced‑stage cancer have shown promising results in enhancing ferroptosis and inhibiting tumor growth. This review explores the intricate relationship between epigenetic regulation and ferroptosis in GICs. Additionally, the potential of leveraging epigenetic modifications to trigger ferroptosis in GICs is investigated. This review highlights the importance of further research to elucidate the specific mechanisms underlying epigenetic control of ferroptosis and to advance the development of novel therapeutic approaches.

Ferroptosis is a regulated form of cell death driven by lipid peroxidation, with 15-lipoxygenase (15LOX) enzyme playing a critical role in catalyzing the oxygenation of polyunsaturated fatty acid-containing phospholipids, such as 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphoethanolamine (SAPE), to initiate this process. The molecular oxygen required for this catalytic reaction is subject to continuous competition among various oxygen-consuming enzymes, which influences the efficiency of lipid peroxidation. In this study, we utilized structure-based modeling and all-atom molecular dynamics simulations to explore the oxygen diffusion pathways in 15LOX-1 under varying oxygen concentrations and in the presence of key components, including a substrate, binding partner PE-binding protein 1 (PEBP1), and the membrane environment. Extensive computational experiments were performed on various system configurations, examining the role of substrate binding, membrane presence, and PEBP1 association in oxygen acquisition. Our computational results indicate that the substrate binding induces a conformational change in 15LOX-1, facilitating the simultaneous recruitment of one or two O2 molecules, which drive peroxidation, leading predominantly to monohydroperoxide products and, less frequently, to dihydroperoxide products. A similar trend was observed in our redox lipidomics analysis. Moreover, we noticed that the presence of the membrane significantly reduces irrelevant oxygen binding spots, directing oxygen molecules toward a primary tunnel essential for the catalytic activity. We identified two primary oxygen tunnels with sequentially and structurally conserved regions across the lipoxygenase family. These findings provide novel insights into the regulation of oxygen acquisition mechanism for LOX members, shedding light on the molecular basis of ferroptosis signaling.

Ferroptosis is a unique mode of cell death driven by iron‑dependent phospholipid peroxidation, and its mechanism primarily involves disturbances in iron metabolism, imbalances in the lipid antioxidant system and accumulation of lipid peroxides. Protein processing, modification and folding in the endoplasmic reticulum (ER) are closely related regulatory processes that determine cell function, fate and survival. The uncontrolled proliferative capacity of malignant cells generates an unfavorable microenvironment characterized by high metabolic demand, hypoxia, nutrient deprivation and acidosis, which promotes the accumulation of misfolded or unfolded proteins in the ER, leading to ER stress (ERS). Ferroptosis and ERS share common pathways in several diseases, and the two interact to affect cell survival and death. Additionally, cell death pathways are not linear signaling cascades, and different pathways of cell death may be interrelated at multiple levels. Ferroptosis and ERS in ovarian cancer (OC) have attracted increasing research interest; however, both are discussed separately regarding OC. The present review aims to summarize the associations and potential links between ferroptosis and ERS, aiming to provide research references for the development of therapeutic approaches for the management of OC.

Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.

Melanoma is highly aggressive, metastatic with a poor prognosis. Despite significant advances in targeted therapies and immunotherapies, their efficiency limited by drug resistance. Tanshinone IIA (Tan IIA), a bioactive compound derived from Traditional Chinese plant, exhibits significant anticancer potential, which still needs more research in its complex regulatory mechanisms.

This study aimed to elucidate the putative targets and regulatory mechanisms of Tan IIA in anti-melanoma, with a focus on its role in inducing ferroptosis.

We designed the experiment to explore the effects of Tan IIA on melanoma through both in vitro and in vivo experiments and to investigate the underlying mechanisms through transcriptomics combining network pharmacology analysis.

Ferroptosis monitored by Malondialdehyde (MDA), Fe2+, reactive oxygen species (ROS) and glutathione (GSH) in vivo and in vitro. RNA sequence was performed to explore the key regulatory pathways involved in Tan IIA-induced ferroptosis. Chromatin immunoprecipitation (ChIP) and Luciferase assays were used to validate transcription factor responsible for prostaglandin-endoperoxide synthase 2 (PTGS2) regulation. Additionally, RT-qPCR, western blot, IF, IHC were aimed to evaluate the expression of target gene.

Tan IIA markedly suppresses melanoma growth in a xenograft model. The same effect performed on inhibition melanoma cells and promotion to ferroptosis with accumulation of ROS, MDA, and Fe²⁺levels and GSH consumption. RNA sequencing and public database analysis revealed that Tan IIA regulates PTGS2, the critical marker of ferroptosis, and PTGS2-knockdown attenuates Tan IIA -induced ferroptosis in melanoma cells. Furthermore, we identified that Tan IIA stimulate signal transducer and activator of transcription 1 (STAT1), a transcription factor, promoting PTGS2 expression and localized in the cell cytoplasm. Moreover, downregulation of the transcription factor STAT1 lead to PTGS2 downregulation and also inhibit ferroptosis in melanoma.

This study, the first to link Tan IIA-induced ferroptosis to the STAT1/PTGS2 axis in melanoma, identifies STAT1 and PTGS2 as novel therapeutic targets for melanoma, which demonstrates the potential of natural compounds Tan IIA in overcoming drug resistance and integrates traditional medicine with advanced molecular techniques for mechanistic exploration.

Increase of immature myeloid cells in the bone marrow drives the development of acute myeloid leukemia (AML). The study aimed to clarify the biological function and regulatory mechanism of scavenger receptor class B type 1 (SR-B1) in AML, mainly its effect on ferroptosis and the influences on leukemogenesis and resistance to venetoclax. In this study, we found that the SR-B1 deficiency directly reduced the invasion and promoted death of malignant cells in AML. Strikingly, SR-B1 deficiency could up-regulated the expression of ferroptosis-related proteins to facilitate the occurrence of ferroptosis in vivo, and could also down-regulated the expression of apoptosis related protein B-cell lymphoma-2 (BCL-2). And then, we confirmed SR-B1 inhibitor block lipid transport-1 (BLT-1) had a superior efficacy in AML cells and AML model mice. The study found that whether SR-B1 deficiency or BLT-1 treatment could cause iron deposition and the accumulation of lipid peroxides in vivo, thereby suppressing leukemogenesis through ferroptosis. Critically, we found that SR-B1 inhibitor BLT-1 could reverse drug-resistance of venetoclax to promote AML cells death via ferroptosis. Our finding identified that SR-B1 as a critical regulator of the proliferation in AML which could provide a promising therapeutic strategy against malignant myeloid leukemia cells and drug-resistance.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases featuring small blood vessel inflammation and organ damage, including necrotizing crescentic glomerulonephritis (NCGN). Persistent vascular inflammation leads to endothelial and kidney cell necrosis. Ferroptosis is a regulated cell death pathway executed by reactive oxygen species and iron-dependent lipid peroxidation culminating in cell membrane rupture. Here we show that ANCA-activated neutrophils induced endothelial cell (EC) death in vitro that was prevented by ferroptosis inhibition with Ferrostatin-1, Liproxstatin-1 and small inhibiting RNA against the enzyme AcylCoA Synthetase Long Chain Family Member 4 (ACSL4). In contrast, neither necroptosis nor apoptosis inhibition affected EC death. Moreover, both ferroptosis inhibitors alleviated lipid peroxide accumulation in EC. Increased lipid peroxidation was detected in kidney sections of AAV mice by immunohistochemistry. We generated MPO-/- ACSL4flox Tie2-Cre+ mice lacking ACSL4 specifically in EC (ACSL4ΔEC) to study the significance of endothelial ferroptosis in vivo. ACSL4ΔEC chimeric mice, but not control mice (ACSL4WT), were protected from NCGN in an MPO-AAV bone-marrow transplantation model. These data establish that EC ferroptosis contributes to ANCA-induced glomerulonephritis. However, systemic pharmacological ferroptosis inhibition with Ferrostatin-1 or Liproxstatin-1 did not protect from NCGN in a murine AAV model. Ferrostatin-1 treatment both directly activated T-cell proliferation and indirectly myeloid-mediated T-cell proliferation and polarization in vitro. Conceivably, both effects may cancel the beneficial effect of endothelial ferroptosis inhibition. Mechanistically, we describe the importance of EC ferroptosis for the development of AAV. However, the lack of protection with systemic pharmacological ferroptosis inhibition should discourage clinicians from evaluating this treatment strategy in clinical AAV studies.

Ovarian cancer is characterized by a high rate of recurrence and a poor prognosis. Ferroptosis, a programmed cell death that is dependent on iron and lipid peroxidation, has emerged as a novel therapeutic target in recent years. This study investigated the effects of Obacunone, a naturally occurring compound present in citrus fruits, on the induction of ferroptosis in ovarian cancer via the Akt/p53 signaling pathway. SKOV3 and OVCAR3 ovarian cancer cell lines were utilized in vitro, while a BALB/c nude mouse model was employed for in vivo experiments. Cell proliferation was assessed utilizing the CCK-8 assay and EDU incorporation. The western blot technique was employed to assess the expression levels of proteins associated with the Akt/p53 signaling pathway. The ferroptosis inhibitor Fer-1 and the Akt activator SC79 were utilized to investigate the potential mechanism of action of Obacunone. Obacunone significantly inhibited the proliferation of ovarian cancer cells and induced ferroptosis, as evidenced by increased intracellular iron content, elevated lipid peroxidation levels, and abnormal mitochondrial morphology. Obacunone also decreased GSH levels, inhibited GPX4 expression and up-regulated ACSL4, as well as reduced Akt phosphorylation and enhanced p53 expression. In vivo experiments showed that Obacunone effectively inhibited tumor growth. Obacunone exhibits potential therapeutic significance through the modulation of the Akt/p53 signaling pathway, which may induce ferroptosis and inhibit the proliferation of ovarian cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) comprises a group of highly malignant tumors of the pancreas. Metabolic reprogramming in tumors plays a pivotal role in promoting cancer progression. However, little is known about the metabolic alterations in tumors that drive cancer drug resistance in patients with PDAC. Here, we identified acyl-CoA thioesterase 8 (ACOT8) as a key player in driving PDAC gemcitabine (GEM) resistance. The expression of ACOT8 is significantly upregulated in GEM-resistant PDAC tissues and is closely associated with poor survival in patients with PDAC. Gain- and loss-of-function studies have shown that ACOT8 drives PDAC GEM resistance both in vitro and in vivo. Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. The combination of orlistat, an ACOT8 inhibitor, and GEM significantly inhibited tumor growth in PDAC organoid and mouse models. This study reveals the biological importance of ACOT8 and provides a potential combination therapy for treating patients with advanced GEM-resistant PDAC.

Intervertebral disc degeneration (IDD) is a type of musculoskeletal system diseases that prevail widely in human society, exerting a substantial economic burden on society. The extensive aggregation of senescent nucleus pulposus (NP) cells within the discs is a significant characteristic of lumbar degenerative alterations. Exploring the underlying mechanisms of NP cell senescence and developing strategies to retard cell senescence are anticipated to become effective approaches for the treatment of IDD.

The study aims to investigate the effects of phosphatidylethanolamine (PE) on autophagic activity, cellular senescence, as well as IDD and dedicated to forging an evidence chain that interconnects IDD, the senescence of NP cells, the autophagic malfunction of NP cells, and the aberrant PE content in NP cells of the advanced-stage group. The resultant outcomes will furnish a theoretical underpinning for the biological prophylaxis and treatment of IDD.

Oxidative stress-induced NP cells senescence is a fundamental characteristic of IDD. To obtain a understanding of the metabolite profile changes in NP cells under stress conditions, Liquid Chromatograph/Mass Spectrometer-based untargeted metabolomics (LC/MS) analysis was utilized in this study. Upon analysis, the distinctive metabolite, PE, which decreased in content in advanced-stage cells, was identified. In this study, Tert-Butyl hydroperoxide (TBHP) was selected as the oxidant to construct an in vitro cellular oxidation model. Methods such as immunofluorescence, immunohistochemistry, Western blotting, and transmission electron microscopy were employed to explore the effects of PE on the senescence of NP cells, the degradation of the extracellular matrix (ECM), and the autophagy of NP cells under stress conditions.

The administration of PE effectively attenuates TBHP-induced cellular senescence and ECM degradation in NP tissue, primarily by stimulating autophagy. Nonetheless, this restorative effect is hindered by chloroquine (CQ), a lysosomal alkalizing agent.

In our study, a series of experiments established a conclusive evidential chain linking IDD, senescence of NP cells, impaired cellular autophagy activity, and abnormal PE content within advanced-stage NP cells. The unique function of PE in promoting NP cells autophagy, thereby delaying cellular senescence, restoring cellular homeostasis, and ECM, suggests its potential as an effective drug for the clinical treatment of IDD.

Ferroptosis is a regulated form of cell death characterised by iron-dependent lipid peroxidation, a process intricately linked to cellular redox homeostasis. This form of cell death is induced by the accumulation of intracellular iron and the subsequent generation of reactive oxygen species (ROS), which leads to lipid peroxidation and ultimately cell death. Ferroptosis is distinct from traditional forms of cell death, such as apoptosis, and holds significant therapeutic potential, particularly in cancers harboring rat sarcoma virus (RAS) mutations, such as epithelial ovarian cancer (EOC). EOC is notoriously resistant to conventional therapies and is associated with a poor prognosis. In this review, we examine recent progress in the understanding of ferroptosis, with a particular focus on its redox biology and the complex regulatory networks involved. We also propose a novel classification system for ferroptosis modulators, grouping them into six categories (I, II, III, IV, V and VI) based on their mechanisms of action and their roles in modulating cellular redox status. By refining these categories, we aim to provide deeper insights into the role of ferroptosis in cancer biology, especially in EOC, and to identify potential therapeutic avenues. We propose that further investigation of ferroptosis in the context of redox biology could reveal novel biomarkers and therapeutic targets, offering promising strategies to overcome resistance mechanisms and improve clinical outcomes for patients with EOC and other treatment-resistant cancers.

Diabetes mellitus is a common chronic metabolic disease, with its prevalence escalating annually. Diabetic cardiomyopathy is a leading cause of mortality among diabetic patients, characterized by intricate metabolic disturbances and myocardial cell demise. Various forms of cellular death pathways including apoptosis, pyroptosis, autophagic cell death, necroptosis, ferroptosis, and entosis have been identified in diabetic cardiomyopathy. Inhibiting myocardial cell death pathways has shown promise in mitigating diabetic cardiomyopathy progression. However, there are still gaps in understanding the role of metal ions in diabetic cardiomyopathy pathogenesis. Recent research endeavors have found that iron, copper, zinc, calcium, manganese and other metal elements related to cell death play an intricate and critical role in the pathogenesis and progression of diabetic cardiomyopathy. Notably, many animal studies have shown that the development and progression of diabetic cardiomyopathy can be alleviated by inhibiting the cell death process induced by these metal ions. Therefore, we review the molecular mechanisms underlying the death of various metal ions and the potential pathophysiological roles they play in diabetic cardiomyopathy. In addition, the value of these metal ions in the treatment of diabetic cardiomyopathy is also described.

Ferroptosis is an attractive therapeutic target in cardiometabolic disease (CMD); however, its contribution to myocardial damage requires further elucidation. This study was designed to examine whether altered phospholipid composition in cardiomyocytes enhanced ferroptosis susceptibility, and the underlying mechanisms. Human iPSC-derived cardiomyocytes and H9c2 cells were used to study iron-induced lipid peroxidation, cell death, and inflammation after exposure to different types of fatty acids. Lipidomic analysis was performed using LC/MS to assess changes in phospholipid composition, with a focus on ω-6 PUFA-containing phospholipids. Cellular and mitochondrial lipid peroxidation, sterile inflammation, and cell death were evaluated. Additionally, the release of damage-associated molecular patterns (DAMPs) and macrophage responses, including STING and type I interferon (IFN-I) signaling, were investigated. LC/MS lipidomic analysis indicated that treating cells with arachidonic acid (AA) elevated ω-6 PUFA-containing phospholipids, particularly phosphatidylethanolamines (PE) and phosphatidylcholines (PC). This significantly increased susceptibility to iron-induced total cellular as well as mitochondrial lipid peroxidation. Subsequently, increased release of mitochondrial DNA to cytosol was detected, resulting in both sterile inflammation and subsequent cell death. Furthermore, iron-induced release of one or more damage associated molecular patterns (DAMP) from AA-treated cells that induced crosstalk with macrophages eliciting a STING and type I interferon (IFN-I) response. These results indicate that cardiomyocytes enriched with ω-6 PUFA-containing phospholipids are more susceptible to lipid peroxidation, underscoring ferroptosis as a critical factor in myocardial damage associated with CMD.

The peroxidation of membrane phospholipids (PLs) is a hallmark of ferroptosis. The endoplasmic reticulum and mitochondria have been implicated in ferroptosis, but whether intracellular PL peroxidation ensues at their contact sites (endoplasmic reticulum-mitochondria contact sites, EMCSs) is unknown. Using super-resolution live imaging, we charted the spatiotemporal events triggered by ferroptosis at the interorganelle level. Here we show that EMCSs expand minutes after localized PL peroxides are formed and secondarily spread to mitochondria, promoting mitochondrial reactive oxygen species and fission. Oxidative lipidomics unravels that EMCSs host distinct proferroptotic polyunsaturated-PLs, including doubly proferroptotic polyunsaturated-acylated PLs, demonstrating their high propensity to undergo PL peroxidation. Endoplasmic reticulum-mitochondria untethering blunts PL peroxidation and ferroptosis, while EMCS stabilization enhances them. Consistently, distancing EMCSs protects the ferroptosis-susceptible triple-negative breast cancer subtype, harbouring high EMCS-related gene expression and basal PL peroxide levels. Conversely, in insensitive triple-negative breast cancer subtypes, bolstering EMCSs sensitizes them to ferroptosis. Our data unveil endoplasmic reticulum-mitochondria appositions as initial hubs of PL peroxide formation and posit that empowering EMCSs endorses ferroptosis in cancer cells.

Ferroptosis, an iron-dependent mode of cell death, has gained prominence for its critical role in the advancement of various cancers, notably clear cell renal carcinoma (ccRCC). The intricacies of ferroptosis's involvement in ccRCC, however, remain largely undefined. This study aimed to dissect the contribution of ferroptosis to ccRCC by examining differentially expressed genes (DEGs) identified within the TCGA ccRCC database and ferroptosis driver genes catalogued in the FerrDb database (dedicates to ferroptosis regulators and ferroptosis-disease associations). We employed 786-O and ACHN ccRCC cell lines, alongside HK2 (human kidey-2) cells and HKC (human kidney cells), to confirm the expression of 9 shared genes. Among these, MIOX (myo-inositol oxygenase) emerged as significantly downregulated in ccRCC cells compared to HK2 and HKC cells. Subsequent survival analysis illuminated a positive correlation between MIOX expression and improved patient survival, underscoring its prognostic significance. Further investigations into MIOX regulation identified four miRNAs via TargetScan predictions, with miR-4537 significantly upregulated in ccRCC cell lines. Functional assays involving miR-4537 mimics and inhibitors, combined with ferroptosis inducers and inhibitors, elucidated its impact on ccRCC cell growth and ferroptosis modulation. The results revealed that miR-4537 expression was diminished following ferroptosis induction, and the miR-4537 inhibitor markedly curbing ccRCC cell proliferation by fostering ferroptosis, while the mimic exerted opposite effects. Mechanistically, miR-4537 targets the 3'-UTR of MIOX to manipulate its expression, ultimately inhibiting ferroptosis in ccRCC cells. Our research indicated that miR-4537 restrained ferroptosis by regulating MIOX in ccRCC, offering novel insights into the mechanisms of ferroptosis in cancer biology and highlighting latent therapeutic avenues for cancer treatment through ferroptosis modulation.

Intervertebral disc degeneration (IVDD) is a prevalent degenerative disease, with low back pain as its primary clinical symptom, imposing significant burdens on individuals and society. With the aging population, IVDD is becoming an inevitable challenge. Current research indicates that the pathogenesis of IVDD is primarily driven by aging, mechanical stress, cell death, and genetics, leading to the loss of nucleus pulposus and degradation of the extracellular matrix within the intervertebral disc.

This review aims to explore the relationship between the mechanisms of ferroptosis and cuproptosis, two newly discovered modes of cell death, and their potential as therapeutic targets for IVDD.

We conducted a comprehensive review of recent studies on ferroptosis and cuproptosis in IVDD, analyzing the mechanisms of these cell death patterns and their potential role in IVDD progression.

Ferroptosis and cuproptosis have been found to be closely related to IVDD. These cell death modes are implicated in the pathological processes of IVDD, suggesting a potential link between their mechanisms and the disease's progression.

The mechanisms of ferroptosis and cuproptosis are closely related to IVDD, and these pathways may be potential targets for IVDD treatment, providing new directions for clinical treatment of IVDD and future research.

Ferroptosis, a distinctive form of cell death induced by iron-dependent lipid peroxidation, is implicated in various biological processes, including liver diseases. Establishing an iron overload-induced ferroptosis model and identifying hepatic gene signatures associated with ferroptosis are crucial for understanding its role in liver pathogenesis.

F-box and leucine-rich repeat protein 5 (FBXL5) is a substrate-recognition component of the SCF E3 ligase complex that restricts intracellular iron levels. In this study, we used liver-specific Fbxl5-null mice to establish an iron overload-induced ferroptosis model. Transcriptome analysis identified genes involved in hepatic ferroptosis. Integrating these gene signatures with another ferroptosis model enabled the assessment of ferroptosis-related pathology in murine liver injury models and in 174 patients undergoing liver resection surgery.

Iron overload induced severe liver damage in liver-specific Fbxl5-null mice, characterized by elevated liver enzymes, histopathological changes, and lipid peroxidation. Transcriptome analysis revealed a distinct set of genes associated with hepatic ferroptosis response. Generating a gene signature for evaluating ferroptosis enhanced the understanding of ferroptosis-related pathologies in liver diseases. Iron overload exacerbated liver damage in murine ischemia-reperfusion injury models via ferroptosis induction. In human patients, elevated serum iron levels correlated with sustained postoperative liver damage, indicating heightened susceptibility to ferroptosis.

Here, a murine model of iron overload-induced hepatic ferroptosis was established, and a gene signature indicative of hepatic ferroptosis response in both mice and humans was identified. These findings underscore the role of ferroptosis in liver injury progression and suggest potential therapeutic targets for liver disease intervention.

Iron is a crucial element for living organism in terms of oxygen transport, hematopoiesis, enzymatic activity, mitochondrial respiratory chain function and also immune system function. The human being has evolved a mechanism to regulate body iron. In some rheumatic diseases such as rheumatoid arthritis (RA), systemic lupus erythematous (SLE), systemic sclerosis (SSc), ankylosing spondylitis (AS), and gout, this balanced iron regulation is impaired. Altered iron homeostasis can contribute to disease progression through ROS production, fibrosis, inflammation, abnormal bone homeostasis, NETosis and cell senescence. In this review, we have focused on the iron metabolism in rheumatic disease and its role in disease progression.