Search Results (187)

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains associated with poor prognosis despite multimodal treatment. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and redox imbalance, has recently emerged as a potential therapeutic vulnerability in glioma. This review summarizes current knowledge on the molecular regulation of ferroptosis in glioma and discusses its implications for tumor progression, therapeutic resistance, and translational targeting. Methods: A structured narrative review of the literature was conducted using PubMed/MEDLINE, Scopus, and Web of Science databases. Experimental, translational, and clinically relevant studies investigating ferroptosis-related mechanisms and therapeutic strategies in glioma and GBM were qualitatively analyzed. Results: Ferroptosis in glioma is regulated by interconnected pathways involving iron metabolism, phospholipid remodeling, oxidative stress, and antioxidant defense systems, particularly the SLC7A11–glutathione–GPX4 axis. Additional protective mechanisms mediated by FSP1 and DHODH, together with regulatory networks involving NRF2, ATF4, p53, and hypoxia-related signaling, contribute to adaptive resistance to ferroptosis. Increasing evidence indicates that ferroptosis interacts bidirectionally with the glioma tumor microenvironment and may exert both antitumor and immunosuppressive effects. Preclinical studies further suggest that ferroptosis induction may enhance the efficacy of temozolomide, radiotherapy, and immunotherapy, although clinical translation remains limited by tumor heterogeneity, blood–brain barrier penetration, and resistance mechanisms. Conclusions: Ferroptosis represents a biologically plausible and therapeutically promising target in glioma. Improved understanding of ferroptosis regulation, tumor microenvironment interactions, and biomarker-guided therapeutic strategies may support the future development of more effective treatments for GBM. Full article

Colorectal cancer (CRC) is a major global health burden characterized by progressive genetic and metabolic alterations, with iron metabolism being increasingly recognized as a key contributor to tumorigenesis. This review provides an integrated synthesis of current evidence on iron metabolism across the continuum of colorectal cancer development, from preneoplastic lesions to advanced disease. We analyzed data from epidemiological, experimental, and mechanistic studies addressing systemic and cellular iron homeostasis, including the hepcidin–ferroportin axis, as well as iron handling within tumor cells and the tumor microenvironment. Available data indicate that colorectal epithelial cells progressively develop an iron-retentive phenotype, characterized by increased iron uptake and reduced export, leading to expansion of the intracellular labile iron pool. This imbalance contributes to oxidative stress, DNA damage, metabolic adaptation, and activation of oncogenic signaling pathways while also influencing immune responses. However, epidemiological findings on dietary iron and CRC risk remain inconsistent, highlighting the context-dependent nature of iron-related effects. In conclusion, iron metabolism represents a dynamic regulator of CRC progression and a mechanistic framework for understanding stage-specific tumor evolution, although further studies are needed to clarify how iron-dependent pathways differ across colorectal tumor subtypes and microenvironmental contexts. Full article

Reductive stress, characterized by excessive reducing equivalents such as NADH, NADPH, and reduced glutathione (GSH), is increasingly recognized as a pathophysiological counterpart to oxidative stress. Chronic hyperinsulinemia and insulin resistance promote this over-reduced state by increasing glucose flux, pentose phosphate pathway activity and de novo lipogenesis, thereby elevating NADPH pools and reshaping cellular lipid composition. While reducing equivalents are essential for biosynthesis and antioxidant defense, persistent over-reduction disrupts redox balance, mitochondrial function and metabolic flexibility. Paradoxically, this reductive metabolic environment may increase susceptibility to ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and failure of glutathione peroxidase 4 (GPX4). Here, we define how reductive stress becomes deregulated in the context of insulin signaling and insulin resistance, and assess whether antioxidant interventions can mitigate ferroptosis, providing a framework for therapeutic strategies to restore redox balance in metabolic disease. Full article

Locally advanced rectal cancer is commonly treated using total neoadjuvant therapy (TNT), which integrates radiotherapy with systemic chemotherapy to improve tumor downstaging, local control, and long-term oncologic outcomes. Despite its central role in treatment, responses to radiotherapy remain highly heterogeneous. While some tumors undergo complete regression, others exhibit intrinsic or acquired treatment resistance, resulting in incomplete tumor control while experiencing treatment-related toxicity. Understanding the biological determinants that govern radiation sensitivity in rectal cancer, therefore, represents a major clinical challenge. Ionizing radiation induces tumor cell death primarily through the generation of reactive oxygen species (ROS) and DNA damage, particularly DNA double-strand breaks. In addition to nuclear DNA injury, radiation-induced oxidative stress can initiate lipid peroxidation within cellular membranes. When lipid peroxide accumulation exceeds the capacity of cellular antioxidant systems, this process can trigger ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid oxidation. Ferroptotic susceptibility is regulated by interconnected metabolic pathways, including cystine transport through system Xc⁻ (SLC7A11/SLC3A2), glutathione synthesis, glutathione peroxidase-4 (GPX4) activity, iron metabolism, and membrane lipid remodeling. Recent evidence further indicates that ferroptosis intersects with antitumor immunity. Ferroptotic tumor cells release oxidized lipid mediators and damage-associated molecular signals that can influence immune activation, while interferon-γ produced by activated CD8⁺ T cells during immune checkpoint blockade suppresses SLC7A11 expression, limiting cystine uptake and promoting ferroptotic tumor cell death. These findings suggest that ferroptosis represents a mechanistic interface between tumor metabolic vulnerability and immune-mediated cytotoxicity. This interaction is particularly relevant in colorectal cancer biology, where immune checkpoint inhibitors demonstrate clinical benefit primarily in tumors with deficient mismatch repair or microsatellite instability-high (MSI-H) status. The vast majority of rectal cancers are microsatellite stable (MSS) and exhibit limited responsiveness to immunotherapy due to reduced immunogenicity and immune exclusion within the tumor microenvironment. Strategies capable of increasing tumor immunogenicity in this setting are therefore of considerable interest. In this review, we examine the molecular mechanisms linking radiation-induced oxidative stress to ferroptosis and tumor immunity in colorectal cancer, while focusing on the clinical context of radiotherapy in rectal cancer. We discuss how lipid metabolism, iron homeostasis, cysteine-dependent antioxidant systems, and immune signaling pathways converge to regulate ferroptotic vulnerability and radiation response. We further explore the therapeutic potential of integrating radiotherapy, ferroptosis-targeting strategies, and immunotherapy to overcome radioresistance and improve treatment outcomes in colorectal cancer. Full article

Background: Macrophages were long regarded as passive executors of erythrophagocytosis responsible for systemic iron recycling. However, increasing evidence has reframed them as immunometabolic hubs that sense diverse environmental cues to modulate systemic iron homeostasis. Main body: This review examines the molecular architecture underlying macrophage iron metabolism and outlines how iron metabolic processes are dynamically regulated across spatial and temporal scales through the integration of mechanotransductive, mitochondrial, and epigenetic signaling pathways. Across disease contexts, macrophage iron handling displays marked heterogeneity, exemplified by contact-dependent iron transfer in tumors and ferroptosis-driven instability in cardiovascular disease. In cardiovascular pathologies, iron overload is associated with enhanced ferroptosis-related cascades that contribute to atherosclerotic plaque instability. Furthermore, at mucosal interfaces, host–pathogen competition over nutritional immunity highlights epigenetic strategies by which pathogens perturb host iron machinery. Conclusions: Linking these mechanistic insights to clinical translation, emerging therapeutic strategies are discussed that move beyond non-specific systemic iron chelation toward more targeted interventions. These include engineering macrophages for targeted drug delivery, exploiting nanomedicine-based redox modulation to influence macrophage phenotypes, and non-invasive regulation via the gut microbiota–epigenetic axis. Collectively, elucidating macrophage iron metabolic networks provides a conceptual framework for the development of precision approaches to inflammatory, metabolic, and malignant diseases. Full article

Background: Emerging evidence has established ferroptosis as a vital factor in the pathogenesis of cardiovascular diseases, especially in septic cardiomyopathy (SCM). Meanwhile, ondansetron (OND), a well-established 5-HT3 receptor antagonist, has gained increasing attention for its pleiotropic effects. However, its potential to modulate ferroptosis in the cardiovascular field remains unexplored. This study aims to fill this gap by exploring the potential of OND as an innovative therapeutic intervention for SCM. Methods: This study utilized both in vitro and in vivo models of septic cardiomyopathy (SCM), which was induced by lipopolysaccharide (LPS) stimulation in neonatal rat cardiomyocytes (NRCMs) and C57BL/6 mice. Through RNA sequencing, as well as molecular and functional assessments—including echocardiography and ferroptosis-related measurements—we revealed the anti-ferroptotic effect of ondansetron (OND). Mechanistically, ATF3 was identified as a pivotal regulator, with its overexpression via AAV9 in vivo and ADV in vitro confirming its role in OND-induced cardioprotection. Results: Ondansetron (OND) showed potent anti-ferroptotic effects in both cellular and murine models of septic cardiomyopathy (SCM). Treatment with OND not only improved cardiac performance but also reduced ferroptotic markers, mitigated lipid peroxidation and iron overload, and bolstered antioxidant defense. Notably, OND administration attenuated oxidative and endoplasmic reticulum (ER) stress while restoring mitochondrial integrity. Mechanistically, the anti-ferroptotic activity of OND was mediated through the HTR3A/ATF3 axis: ATF3 overexpression negated OND’s protective effects, while HTR3A antagonism with VUF10166 recapitulated its benefits. Conversely, HTR3A agonism with PBG attenuated ferroptosis resistance, further implicating this pathway as central to OND’s mechanism. Conclusions: This study demonstrated a novel pharmacological role for ondansetron (OND) in attenuating ferroptosis in septic cardiomyopathy (SCM) via the HTR3A/ATF3 signaling pathway. This finding delineates a novel therapeutic avenue and supports the repurposing of OND beyond its traditional antiemetic use to cardiovascular applications. Full article

The lung–kidney axis forms an important physiologically integrated system which controls multiple essential functions of the body. An important observation of this interaction is tissue oxygenation and erythropoiesis, a vital process that involves erythropoietin (EPO) release by the kidney to bring red cell production into the bone, while pulmonary gas exchange ensures adequate oxygen delivery to the cells. Subsequently, the lung–kidney activation of the renin angiotensin system (RAS) influences vascular tone, blood pressure, and tissue perfusion, influencing the delivery of oxygen and the body’s requirement for erythropoietin. Additionally, beyond oxygen sensing, studies have evidenced the role of hypoxia-inducible factors (HIFs), inflammatory mediators, endothelial signaling pathways and iron availability. These modulate erythropoietin production, which enhances the process of erythropoiesis and arterial oxygen balance. Localized variations in renal oxygen levels together with hemodynamic control mechanisms enable the body to produce erythropoietin independently from systemic hypoxia conditions. This concept emerged to include the renal oxygen extraction fraction (OFE) and intrarenal microvascular shunting with perfusion oxygen coupling in governing EPO production. The present review refines the traditional knowledge to further expand our understanding of the lung–kidney axis regulating the process of erythropoiesis and arterial oxygen content. The integrative framework demonstrates that pulmonary arterial oxygenation and renal oxygen sensing together with bone hematopoietic responses operate as a unified system which maintains both oxygen equilibrium and hematopoietic balance throughout the body. Full article

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and oxidative stress, increasingly implicated in cancer biology. However, its molecular regulation across breast cancer subtypes and its potential systemic manifestations remain incompletely understood. The aim of this study was to identify ferroptosis-associated molecular alterations that are largely shared across subtypes and to evaluate their systemic reflection following localized tissue injury. Tumor and matched normal breast tissues representing major molecular subtypes were analyzed. Global mRNA and miRNA expression profiling was performed using microarrays, followed by validation of selected genes using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Functional enrichment and protein–protein interaction analyses were conducted to characterize associated pathways. In addition, systemic responses were assessed in patients undergoing fibroadenoma cryoablation through longitudinal blood sampling. Six ferroptosis-related genes (SLC7A11, GPX4, FTH1, NQO1, NFE2L2, SQSTM1) demonstrated consistent upregulation across all breast cancer subtypes, with higher expression observed in more aggressive tumors. These genes are functionally linked to antioxidant defense, iron metabolism, and oxidative stress regulation, and their coordinated expression pattern is consistent with activation of NRF2-dependent cytoprotective pathways. Downregulation of selected miRNAs may contribute to this expression profile but likely represents a secondary regulatory mechanism. Survival analysis revealed heterogeneous and subtype-dependent associations, with limited and gene-specific prognostic relevance. Cryoablation induced transient increases in circulating levels of the analyzed proteins, reflecting systemic responses to localized tissue injury. In conclusion, breast cancer is characterized by a largely shared ferroptosis-associated molecular signature across subtypes; however, its clinical impact appears to be variable and context-dependent. Systemic detection of related molecular signals suggests potential utility as indicators of tissue stress responses, although their role as specific biomarkers of ferroptosis requires further validation. Full article

Differentiated thyroid cancer (DTC), including papillary and follicular subtypes, is generally associated with favorable prognosis; however, a subset of patients develops recurrent, metastatic, or radioiodine-refractory diseases with limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a biologically relevant process in thyroid cancer, yet its role in differentiated disease remains incompletely defined. Unlike many other malignancies, thyroid cancer arises within an organ intrinsically shaped by iodine-dependent redox reactions required for thyroid hormone biosynthesis. This unique oxidative environment imposes selective pressure on tumor cells to adapt redox balance, lipid metabolism, and antioxidant defenses, all of which are central regulators of ferroptosis. Accumulating evidence indicates that ferroptosis susceptibility in DTC is dynamically modulated by differentiation status, oncogenic signaling, metabolic rewiring, and tumor microenvironmental interactions. Notably, progression toward radioiodine-refractory disease is accompanied by dedifferentiation and reinforcement of anti-ferroptotic programs, linking ferroptosis resistance to therapeutic failure. In this review, we synthesize recent original studies and contemporary reviews to provide a focused overview of ferroptosis in DTC, excluding anaplastic disease. We discuss thyroid-specific redox and iodine metabolism, genetic and metabolic determinants of ferroptosis sensitivity, lipid remodeling, and immune–microenvironmental interactions, and highlight translational opportunities for targeting ferroptosis in radioiodine-refractory DTC. By reframing ferroptosis as a context-dependent vulnerability rather than a universal death pathway, this review outlines a conceptual roadmap for integrating ferroptosis modulation into existing therapeutic strategies for DTC. Full article

Background: Extracellular vesicles (EVs) released from skeletal muscle mediate metabolic communication via microRNAs (miRNAs). While both circadian rhythms and exercise influence metabolism, the joint modulation of the muscle-derived EV miRNA landscape by circadian rhythms and chronic exercise remains undefined, particularly under the metabolic stress of obesity. Methods: Employing a 2 × 2 factorial design (Phase: ZT3 vs. ZT15; Condition: sedentary vs. exercise; ZT, Zeitgeber Time), EV-enriched fractions were isolated from ex vivo quadriceps muscle (QUA) cultures of high-fat diet-fed mice following an 8-week treadmill training regimen using polymer-based precipitation, and comprehensive miRNA profiling was performed by small RNA sequencing. Results: Principal component analysis (PCA) revealed that circadian phase accounted for a greater proportion of global variance in EV miRNA profiles than exercise. Differential expression analysis identified miR-1a-3p and miR-1b-5p as upregulated across both composite phase and exercise contrasts; however, condition-specific analyses indicated that this signal was primarily driven by the sedentary-phase comparison (ZT15-sed vs. ZT3-sed), in which the miR-29 family was also prominently co-upregulated, rather than constituting independent phase and exercise effects; this phase-associated signature was absent in the corresponding exercise-condition comparison. Exploratory functional enrichment of experimentally validated targets revealed phase-preferential association with metabolic and iron–heme pathways, whereas exercise-associated miRNAs mapped to signaling, inflammatory, and transcription-related networks. Conclusions: Circadian phase was the dominant contributor to global variance in muscle-derived EV-enriched miRNA profiles in obesity, as reflected by the phase-associated separation along principal component 1 (PC1, 33.47% of total variance), with exercise introducing context-dependent adaptive modulation. This study provides a foundational basis for investigating the temporal regulation of muscle secretome dynamics under high-fat diet conditions, highlighting temporal specificity as a key dimension in EV-mediated exercise physiology research. Full article

Background/Objectives: Dihydroartemisinin (DHA), a bioactive metabolite of Artemisia annua, displays potent antitumor activity in multiple cancers. However, its dose-dependent transcriptional regulatory networks in colorectal cancer (CRC) remain insufficiently understood. This study aimed to clarify the molecular mechanisms of low- and high-dose DHA in human CRC cells and reveal the dose-dependent crosstalk among related biological processes. Methods: We integrated RNA-seq transcriptomic profiling and functional validation in HCT116 cells treated with 20 μM (low-dose) or 50 μM (high-dose) DHA. Differentially expressed genes (DEGs) were screened at FDR ≤ 0.05 and |log₂(fold change)| ≥ 1, followed by GO and KEGG enrichment analyses. Results: DHA inhibited cell viability dose-dependently, with an IC₅₀ of 50 μM. We identified 280 and 678 DEGs in low-and high-dose groups, respectively. Low-dose DHA induced apoptosis via GADD45α/β and ATF4/DDIT3-mediated endoplasmic reticulum stress and triggered senescence through G2/M phase arrest. High-dose DHA mainly modulated gene expression signatures associated with ferroptosis by regulating iron homeostasis and lipid peroxidation at the transcriptional level. Both doses suppressed glycolysis, lipid, and folate metabolism; high-dose DHA also inhibited MGAT5B-mediated glycosylation. DHA regulated five core signaling pathways dose-dependently, with high-dose DHA further repressing Wnt3a/16 and BMP4/6. Conclusions: This study first identifies ferroptosis-related gene networks as key transcriptional targets. It reveals dose-dependent crosstalk among cell death, senescence, metabolic reprogramming, and signaling, providing a transcriptomic framework and gene targets for optimizing DHA-based colorectal cancer therapy. Full article

Hepatic ischemia–reperfusion injury (HIRI) is a significant clinical challenge in the field of liver surgery and transplantation, and its pathological mechanisms are complex. In recent years, ferroptosis, a novel form of iron-dependent programmed cell death, plays a central role in this injury process. G protein-coupled receptors (GPCRs), as the largest family of membrane receptors in the body, regulate cellular stress and death through extensive signaling networks. This review elucidates the specific molecular mechanisms by which GPCRs regulate ferroptosis in HIRI by affecting key pathways such as lipid peroxidation, iron metabolism homeostasis, and antioxidant defense. It further explores potential therapeutic strategies targeting specific GPCRs to modulate ferroptosis, thereby alleviating liver injury and improving postoperative outcomes, to provide new insights and a theoretical basis for clinical translation. Full article

Background: Transmissible gastroenteritis virus (TGEV) is a highly pathogenic porcine coronavirus that causes severe gastrointestinal damage in piglets. However, how TGEV affects host iron homeostasis, oxidative stress, and the ferroptosis process remains unclear. This study aimed to investigate the effects of TGEV infection on cellular iron metabolism, oxidative damage, and lipid peroxidation-mediated ferroptosis, as well as to evaluate the potential therapeutic role of retinoic acid (RA). Methods: Using an intestinal epithelial cell model of TGEV infection, we assessed key regulators of iron handling, oxidative stress, lipid peroxidation, and ferroptosis. The expression of ferroportin (FPN) and ferritin (FTH/L) and the activity of the p62–NRF2–GPX4/HO-1 antioxidant axis were analyzed, and the effects of exogenous RA treatment on these endpoints were examined. Results: TGEV infection disrupted cellular iron homeostasis by downregulating the expression of ferroportin (FPN) and ferritin (FTH/L), leading to the accumulation of intracellular free iron, which in turn induced the generation of a large amount of reactive oxygen species (ROS) and ultimately triggered ferroptosis in intestinal epithelial cells. Additionally, TGEV infection significantly inhibited the p62-NRF2-GPX4/HO-1 antioxidant signaling pathway, further exacerbating the ferroptosis process. Conclusions: This study reveals that ferroptosis is a key pathological mechanism in TGEV-induced intestinal injury and demonstrates that RA exerts a therapeutic effect by regulating iron metabolism and activating the p62-NRF2-GPX4/HO-1 signaling pathway. These findings provide new theoretical insights for potential intervention strategies targeting virus infection-associated ferroptosis and intestinal damage. Full article

Psoriasis is classically defined as an immune-mediated disease. However, many patients do not achieve durable remission after immune-targeted therapies, suggesting that further pathogenic mechanisms may contribute to the persistence of psoriasis. Here, we propose ferroptosis, an iron-dependent regulated cell death driven by lipid peroxidation and failure of lipid repair, as a potential link between metabolic stress and immune-mediated inflammation in psoriasis. We summarize experimental evidence showing that membrane lipids remodeling, antioxidant suppression, lipid peroxidation, and dysregulated iron handling together define ferroptosis-permissive niches within psoriatic lesions. We also discuss functional studies demonstrating that ferroptosis modulation can reshape psoriasiform inflammation and explore how ferroptotic stress may amplify inflammatory signaling at the immune-epidermal interface, reinforcing IL-17/TNF/IFN-γ pathways. Finally, we discuss ferroptosis-related transcriptomic signatures as a potential approach to stratify psoriasis, capturing metabolic features that are not reflected by cytokine profiling. The translational opportunities and constraints for ferroptosis-targeted interventions are outlined, highlighting epidermal redox homeostasis as a new therapeutic frontier in psoriasis. Full article

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, emerged as an important contributor to the pathogenesis of diabetes and its complications. Impaired glucose and iron metabolism, and increased oxidative stress, predispose cells—particularly pancreatic β-cells and vascular tissues—to ferroptotic cell death, contributing to β-cell dysfunction, insulin resistance, and the progression of diabetic complications. Hydrogen sulfide (H₂S), an important gasotransmitter, plays a pivotal role in regulating various pathophysiological processes by interfering with key cellular signaling pathways, including those related to cell death. In the context of ferroptosis, H₂S exerts protective effects by activating the nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4/glutathione (Nrf2/GPX4/GSH) axis, enhancing cellular antioxidative defenses and inhibiting lipid peroxidation. Furthermore, H₂S modulates key regulators of iron homeostasis and lipid metabolism, including hepcidin, ferritin, and the cystine/glutamate antiporter system (xCT) antiporter, further attenuating ferroptosis. Exogenous administration of H₂S can reverse ferroptosis-induced cellular injury in several pathological settings and improve metabolic outcomes in diabetic models. These findings suggest that targeting H₂S signaling is a promising therapeutic strategy to inhibit ferroptosis and mitigate diabetes-related organ dysfunction. This review summarizes current insights into the molecular interplay between H₂S and diabetes-related signaling pathways, primarily ferroptosis, emphasizing the antiferroptotic therapeutic potential of H₂S-based interventions for the prevention and treatment of diabetic complications. Full article