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.

A significant role in many cancers is played by cuproptosis, a new term for the copper-dependent regulatory cell death pattern. However, as a new research hotspot, the cuproptosis-related lncRNAs (CRLs) associated with regulation in oral squamous cell carcinoma (OSCC) patients are currently not well understood.

Long noncoding RNA (lncRNA) data were downloaded from the Cancer Genome Atlas database (TCGA). The 'LIMMA' package in R software was used to screen for differential expression of CRLs. LASSO regression and COX regression models were used to construct prognostic signature based on 4 prognostic CRLs. Finally, the relationship of risk characteristics with immune correlation analysis, somatic mutations, PCA, biological molecular pathways and drug sensitivity was investigated.

A cuproptosis-related lncRNAs prognostic signature was developed by us. Based on the risk scores, the OSCC samples were split into high- and low-risk groups using this signature. The two risk groups differed significantly in immune functions, drug sensitivity, and overall survival. The risk model showed better prognostic predictive power compared to the traditional clinicopathological signature. By qPCR trial, we also verified the expression of STARD4-AS1 in OSCC cell lines and tissues was in line with our results from this experimental screen. Through cell experiments, we have confirmed that knocking down STARD4-AS1 promotes the proliferation and migration ability of OSCC cells.

The CRLs signature contributes to new understandings of the treatment of OSCC and is a rubost biomarker for predicting the prognosis of patients with OSCC.

Ferroptosis, a regulated form of cell death characterized by iron-dependent phospholipid peroxidation, remains poorly understood in the context of esophageal cancer development and its regulatory mechanisms. Through comprehensive bioinformatic analyses, we identified ferroptosis-related pathways as crucial mediators in esophageal cancer progression, with ZIP8 emerging as a key regulatory element. We observed significant upregulation of ZIP8 in esophageal cancer specimens, which correlated with poor clinical outcomes. Functional studies demonstrated that ZIP8 depletion significantly attenuated cellular proliferation in vitro. Mechanistically, elevated ZIP8 expression enhanced zinc-dependent phosphorylation of CREB, leading to upregulation of the ferroptosis suppressor GPX4 and inhibition of this iron-dependent cell death modality. Significantly, we discovered that the natural compound Nobiletin targeted ZIP8, inhibiting Esophageal squamous cell carcinoma (ESCC) cell growth in vitro and in vivo. Our findings demonstrate ZIP8 as a potential therapeutic target in ESCC and suggest that promoting ferroptosis through ZIP8 inhibition may represent a novel anti-cancer strategy for ESCC therapy.

This paper focuses on the mechanism underlying nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and subsequent hepatocyte ferroptosis. Iron is a pivotal trace element, but excessive iron deposition can lead to liver injury. Ferroptosis is a recognized, iron-dependent mode of programmed cell death that plays an important role in various liver diseases. NCOA4 is a key molecule mediating the selective autophagic degradation of ferritin. It affects ferroptosis by regulating intracellular free iron levels. NCOA4 expression is regulated by various factors, including cellular iron levels and oxidative stress. It was demonstrated that inhibition of NCOA4 can reduce iron-mediated cell death and mitigate liver damage, suggesting that NCOA4 may be a potential target for the prevention and treatment of liver diseases. Further in-depth studies of the molecular mechanism of NCOA4-mediated ferritinophagy and its relationship with iron-induced cell death can provide novel ideas for the diagnosis and treatment of liver diseases. The deficiency or abnormal expression of NCOA4 is closely associated with ferroptosis in a variety of liver diseases, including non-alcoholic fatty liver disease, alcoholic liver disease, drug-induced liver injury, and liver fibrosis. Future studies should focus on elucidating the dynamic changes in the NCOA4 regulatory network during specific pathological processes. This strategy can lay the foundation for drug development.

SCARA5 (Scavenger Receptor Class A Member 5), a member of scavenger receptor class A, is a type II transmembrane protein. Previous studies, including our own, have suggested that SCARA5 acts as a tumor suppressor in various cancers. Additionally, SCARA5 has been identified as a ferritin receptor that facilitates iron delivery independent of transferrin. However, it remains unclear whether ferroptosis is involved in the tumor-suppressive function of SCARA5 in hepatocellular carcinoma (HCC). In this study, we found that SCARA5-deficient cells, including mouse embryonic fibroblasts (MEFs) and HCC cells, exhibited reduced sensitivity to ferroptosis induced by erastin and RSL3. We measured the cell viability, cellular reactive oxygen species (ROS), lipid ROS, malondialdehyde (MDA) and ferrous iron concentration to assess the role of SCARA5 in ferroptosis. Mechanistically, we confirmed that SCARA5 might enhance the intracellular availability of bioactive ferrous iron by promoting autophagic degradation of the major iron storage protein ferritin. Furthermore, we found that SCARA5 deficiency contributed to the resistance of HCC cells to sorafenib, a therapeutic agent for HCC, possibly by inhibiting ferroptosis. Collectively, our study revealed the role of SCARA5 in regulating ferroptosis, providing a profound understanding of sorafenib resistance in HCC systemic therapy.

Cardiomyocyte loss by regulated death modes, like apoptosis and ferroptosis, has been implicated in the development of dilated cardiomyopathy (DCM). It remains unclear whether cardiomyocyte ferroptosis occurs as a consequence of Hippo pathway activation. Using a mouse model of DCM by overexpression of Mst1 transgene (Mst1-TG) leading to Hippo pathway activation, we showed that cardiomyocyte ferroptosis was evident by transcriptomic profiles, elevated mitochondrial Fe2+ content, increased levels of lipid peroxidation and obvious mitochondrial damage. Transcriptome revealed significant alterations of genes participating in iron metabolism and lipid peroxidation. Treatment of Mst1-TG mice with the ferroptosis inhibitor ferrostatin-1 reduced cardiomyocyte ferroptosis and improved cardiac function. Using heart samples from human patients with DCM, we also found significant cardiomyocyte loss and lipid peroxidation. In cultured cardiomyocytes, ferroptosis was induced by treatment with erastin or YAP inhibitor verteporfin, and cell ferroptosis under these conditions was largely prevented by either iron chelation or Mst1 gene knockdown. In a strain of transgenic mice with cardiomyocyte inactivation of Mst1 (dnMst1-TG), erastin-induced ferroptosis and cardiac dysfunction, seen in control mice, were mitigated. Mechanistically, nuclear YAP and YY1 were shown to interact and bind to the Nfs1 promoter, thus mediating downregulation of Nfs1 (encoding cysteine desulfurase). Subsequent inhibition of iron-sulfur cluster (ISC) biosynthesis promoted cardiomyocyte ferroptosis and DCM phenotype. Restoration of Nfs1 expression was achieved by treatment of Mst1-TG mice with AAV9-Nfs1 virus, which alleviated ferroptosis, mitochondrial damage and DCM phenotype. In conclusion, in the DCM model with Hippo pathway activation, our findings unravel that NFS1 downregulation occurs and leads to insufficient ISC biosynthesis and cardiomyocyte ferroptosis. Our findings implicate that restoration of cardiomyocyte NFS1 level may represent a new therapeutic strategy for DCM.

Metabolic shifts in cancer cells were found to participate in tumorigenesis, especially driving chemotherapeutic resistance. Ferroptosis is a newly discovered form of cell death induced by excessive accumulations of iron and lipid peroxidation. Susceptibility to ferroptosis can be intrinsically regulated by various cellular metabolic pathways. Therefore, inducing ferroptosis might be a promising anticancer therapeutic strategy. DEAD-box helicase 3 X-linked (DDX3X), a critical modulator of RNA metabolism, was identified as an oncogene in breast cancer and also participates in cancer metabolism and chemotherapeutic resistance. However, the molecular regulation of the association between DDX3X and ferroptosis is largely unknown. Herein, we investigated the correlation between resistance to ferroptosis and DDX3X expression in breast cancer cells. We found that elevation of DDX3X was associated with increased resistance to a ferroptosis inducer in breast cancer cells, and manipulating DDX3X expression regulated the sensitivity to the ferroptosis inducer. Importantly, DDX3X upregulated expression of the anti-ferroptotic enzyme glutathione peroxidase 4 (GPX4) gene to confer ferroptosis resistance in breast cancer cells. Moreover, DDX3X was transcriptionally upregulated by the yes-associated protein (YAP). Knockdown of YAP downregulated DDX3X mRNA expression and facilitated lipid peroxidation, but that were restored in the presence of DDX3X. Clinically, coexpression of DDX3X and YAP was found in a variety of malignancy, and their elevation conferred poor survival prognosis in patients with breast cancer. Together, our findings reveal the crucial role of DDX3X in sensitivity to ferroptosis and underscore its potential as a diagnostic marker and therapeutic target. DDX3X renders resistance to ferroptosis and plays a role in mitigating lipid peroxidation, paving the way for therapeutic vulnerability via targeting cancer metabolism.

Aging is a natural biological process that is characterized by the progressive decline in physiological functions and an increased vulnerability to age-related diseases. The aging process is driven by different cell and molecular mechanisms. It has recently been shown that aging is associated with heightened vulnerability to ferroptosis (an intracellular iron-dependent form of programmed cell death). This susceptibility arises from various factors including oxidative stress, impaired antioxidant defences, and dysregulated iron homeostasis. The progressive decline in cellular antioxidant capacity and the accumulation of damaged components contribute to the increased susceptibility of aging cells to ferroptosis. Dysregulation of key regulators involved in ferroptosis, such as glutathione peroxidase 4 (GPX4), iron regulatory proteins, and lipid metabolism enzymes, further exacerbates this vulnerability. The decline in cellular defence mechanisms against ferroptosis during aging contributes to the accumulation of damaged cells and tissues, ultimately resulting in the manifestation of age-related diseases. Understanding the intricate relevance between aging and ferroptosis holds significant potential for developing strategies to counteract the detrimental effects of aging and age-related diseases. This will subsequently act to mitigate the negative consequences of aging and improving overall health in the elderly population. This review aims to clarify the relationship between aging and ferroptosis, and explores the underlying mechanisms and implications for age-related disorders, including neurodegenerative, cardiovascular, and neoplastic diseases. We also discuss the accumulating evidence suggesting that the imbalance of redox homeostasis and perturbations in iron metabolism contribute to the age-associated vulnerability to ferroptosis.

Emerging evidence emphasizes the critical role of alternative polyadenylation (APA) in posttranscriptional regulation of genes, and APA-associated genetic variants (apaQTLs) show particular relevance for multiple disease. However, genetic regulation of APA and its role in non-small cell lung cancer (NSCLC) risk have not been thoroughly studied. Here, by leveraging genotype and APA data from The Cancer Genome Atlas, the association between genetic variation and APA is determined in NSCLC samples. The identified apaQTLs are distinct from eQTLs and are preferentially enriched in functionally relevant characteristics, including poly(A) motifs, APA-associated RBP binding sites, functional elements, and known NSCLC risk loci. Moreover, genes associated with apaQTLs are broadly involved in cancer-related biological process. Of note, integration of apaQTL variants with traditional GWAS-derived PRS is proved as a potential screening tool for NSCLC. By integrating large-scale population and biological experiments, a functional apaQTL variant rs9606 in LYRM4 is identified. Mechanistically, rs9606 induces aberrant APA process of LYRM4 via allele-specific interacting with NUDT21, which lead to increased expression of oncogene LYRM4 and thus contribute to NSCLC risk. This study demonstrates the distinct contribution of APA-associated genetic variants in NSCLC risk, providing critical clues and potential targets for NSCLC etiology and clinical intervention.

The expression of Family with sequence similarity 207 member A( FAM207A) is closely related to the development, growth, and progression of various cancers. However, extensive research into its biological functions remains unexplored. In this study, we conducted a comprehensive biological information analysis of the Lung adenocarcinoma (LUAD) dataset to elucidate the foundational mechanisms underlying FAM207A's role in tumor development. The expression and clinical information of LUAD patients for FAM207A were extracted from the Cancer Genome Atlas (TCGA). Using Western blot, we assessed the expression levels of relevant proteins in LUAD cells and human lung epithelial cells. Subsequently, we employed Cox regression analysis to evaluate the prognostic significance of FAM207A in LUAD, along with gene set enrichment analysis (GSEA) to explore its potential biological functions and interactions with FAM207A's immune microenvironment. Finally, in vitro experiments confirmed that FAM207A significantly influences the proliferation and migration of LUAD cells. The results indicate that FAM207A mRNA and protein expression levels in LUAD tissues and cell are significantly elevated. Additionally, FAM207A high expression is significantly associated with a shorter overall survival (OS) and more advanced pathological stages. Furthermore, FAM207A expression is significantly linked to the expression of immunogenic markers in the LUAD tumor microenvironment. Gene set and KEGG enrichment analyses revealed that FAM207A is primarily associated with genes involved in adhesion and immune signaling pathways. Additionally, in vitro experiments demonstrated that FAM207A can effectively promote the proliferation and migration of LUAD cells. Our findings revealed that FAM207A is overexpressed in LUAD and is linked to a poor prognosis. Our study demonstrates the potential of FAM207A as an immunotherapeutic and predictive biomarker in LUAD.

Since its introduction in 2012, ferroptosis has garnered significant attention from researchers over the past decade. Unlike autophagy and apoptosis, ferroptosis is an atypical iron-dependent programmed cell death that falls under necrosis. It is regulated by various cellular metabolic and signaling processes, which encompass amino acid, lipid, iron, and mitochondrial metabolism. The initiation of ferroptosis occurs through iron-dependent phospholipid peroxidation. Notably, ferroptosis exhibits a dual effect and is associated with various diseases. A significant challenge lies in managing autoimmune disorders with unknown origins that stem from the reactivation of the immune system. Two contributing factors to autoimmunity are the aberrant stimulation of cell death and the inadequate clearance of dead cells, which can expose or release intracellular components that activate the immune response. Ferroptosis is distinct from other forms of cell death, such as apoptosis, necroptosis, autophagy, and pyroptosis, due to its unique morphological, biochemical, and genetic characteristics and specific relationship with cellular iron levels. Recent studies indicate that immune cells can both induce and undergo ferroptosis. To better understand how ferroptosis influences immune responses and its imbalance in disease, a molecular understanding of the relationship between ferroptosis and immunity is essential. Consequently, further research is needed to develop immunotherapeutics that target ferroptosis. This review primarily focuses on the role of ferroptosis in immune-related disorders.

Frataxin is a small protein involved in the rare disease Friedreich's ataxia. During the last few years, significant knowledge has been gained concerning frataxin folding, structure, dynamics, and function. In eukaryotic organisms, it is located in the mitochondrial matrix, and recently, its macromolecular context was revealed. This protein is part of a decameric supercomplex consisting of six subunits required for iron-sulfur cluster assembly, where two of them alternate in a mutually exclusive manner. Regarding Frataxin, pathogenic variants were studied, and while some exhibited reduced conformational stability, others presented an altered function. In this review, we focused on different aspects concerning the biophysics and the biochemistry of frataxin and its partners, as well as on the current knowledge regarding proteostasis and post-translational modifications. The involvement of frataxin and its partners in diseases will also be addressed, including the current therapeutic approaches. Finally, a section is dedicated to understanding the phylogenetic distribution of frataxin.

We present here a comprehensive update on recent advancements in the field of ferroptosis, with a particular emphasis on its metabolic underpinnings and physiological impacts. After briefly introducing landmark studies that have helped to shape the concept of ferroptosis as a distinct form of cell death, we critically evaluate the key metabolic determinants involved in its regulation. These include the metabolism of essential trace elements such as selenium and iron; amino acids such as cyst(e)ine, methionine, glutamine/glutamate, and tryptophan; and carbohydrates, covering glycolysis, the citric acid cycle, the electron transport chain, and the pentose phosphate pathway. We also delve into the mevalonate pathway and subsequent cholesterol biosynthesis, including intermediate metabolites like dimethylallyl pyrophosphate, squalene, coenzyme Q (CoQ), vitamin K, and 7-dehydrocholesterol, as well as fatty acid and phospholipid metabolism, including the biosynthesis and remodeling of ester and ether phospholipids and lipid peroxidation. Next, we highlight major ferroptosis surveillance systems, specifically the cyst(e)ine/glutathione/glutathione peroxidase 4 axis, the NAD(P)H/ferroptosis suppressor protein 1/CoQ/vitamin K system, and the guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin/dihydrofolate reductase axis. We also discuss other potential anti- and proferroptotic systems, including glutathione S-transferase P1, peroxiredoxin 6, dihydroorotate dehydrogenase, glycerol-3-phosphate dehydrogenase 2, vitamin K epoxide reductase complex subunit 1 like 1, nitric oxide, and acyl-CoA synthetase long-chain family member 4. Finally, we explore ferroptosis's physiological roles in aging, tumor suppression, and infection control, its pathological implications in tissue ischemia-reperfusion injury and neurodegeneration, and its potential therapeutic applications in cancer treatment. Existing drugs and compounds that may regulate ferroptosis in vivo are enumerated.

Evidence suggests that corneal endothelial cell (CEC) death in Fuchs endothelial corneal dystrophy (FECD) is due to ferroptosis, an iron-mediated cell death. Iron-sulfur cluster (ISC)-containing aconitases and the iron responsive element binding proteins IREBP1 and IREBP2 are known mediators of iron homeostasis. This study investigates mechanisms underlying iron dysregulation in CECs and proposes a role for ISCs and IREBPs in the context of FECD pathogenesis.

We studied gene expression of proteins responsible for ISC synthesis and iron homeostasis in human and mouse CECs and analyzed published RNA sequencing datasets. We validated a subset of transcriptional changes between FECD and control tissues using microfluidic Western blotting with human CEC tissues. Finally, we silenced proteins involved in ISC synthesis or iron homeostasis in cell cultures and assessed ferroptosis susceptibility.

RNA-seq and qPCR data demonstrated significantly decreased transcription of genes required for ISC synthesis in FECD tissues (P < 0.05). Protein quantification revealed a significant decrease in mitochondrial aconitase (P < 0.05), ferredoxin 1 (P < 0.001), and mitofusin (P < 0.05), and a significant increase in cysteine desulfurase (P < 0.05), cytosolic aconitase/IREBP1, and IREBP2 (P < 0.05) in FECD tissues. Silencing studies revealed increased susceptibility to ferroptosis upon siRNA knockdown of ferredoxin 1 (P < 0.05).

We identified differential gene expression of proteins responsible for ISC synthesis, ISC-containing proteins, IREBPs that mediate cellular iron homeostasis, and mitofusin, which promotes mitochondrial fusion in FECD. We also identified increased susceptibility to ferroptosis after ferredoxin 1 knockdown in CECs. These results advance an ISC- and IREBP-mediated mechanism of iron accumulation in FECD CECs.

Ferroptosis represents an emerging, iron-dependent form of cell death driven by lipid peroxidation. In recent years, it has garnered significant attention in the realm of cancer immunotherapy, particularly in studies involving immune checkpoint inhibitors. This form of cell death not only enhances our comprehension of the tumor microenvironment but is also considered a promising therapeutic strategy to address tumor resistance, investigate immune activation mechanisms, and facilitate the development of cancer vaccines. The combination of immunotherapy with ferroptosis provides innovative targets and fresh perspectives for advancing cancer treatment. Nevertheless, tumor cells appear to possess a wider array of ferroptosis evasion strategies compared to CD8+T cells, which have been conclusively shown to be more vulnerable to ferroptosis. Furthermore, ferroptosis in the TME can create a favorable environment for tumor survival and invasion. Under this premise, both inducing tumor cell ferroptosis and inhibiting T cell ferroptosis will impact antitumor immunity to some extent, and even make the final result run counter to our therapeutic purpose. This paper systematically elucidates the dual-edged sword role of ferroptosis in the antitumor process of T cells, briefly outlining the complexity of ferroptosis within the TME. It explores potential side effects associated with ferroptosis-inducing therapies and critically considers the combined application of ferroptosis-based therapies with ICIs. Furthermore, it highlights the current challenges faced by this combined therapeutic approach and points out future directions for development.

Insufficient microwave ablation (IMWA) is linked to aggressive hepatocellular carcinoma (HCC) progression. An increase in lactate levels after sublethal heat stress (HS) has been confirmed in HCC. However, the role of lactate-related histone lactylation in the progression of HCC caused by sublethal HS remains unclear. Here, we found that the metastatic potential of HCC increased in a lactate-dependent manner after IMWA. Moreover, sublethal HS triggered an increase in H3K18la modification, as validated in a cell-derived xenograft mouse model and human HCC samples. By performing an integrated analysis of proteomic and transcriptomic profiles, we revealed that HCC cells exhibited increased intracellular iron ion homeostasis and developed resistance to platinum-based drugs after exposure to sublethal HS. We subsequently integrated proteomic and transcriptomic data with H3K18la-specific chromatin immunoprecipitation (ChIP) sequencing to identify candidate genes involved in sublethal heat treatment-induced HCC cell metastasis. Mechanically, an increase in H3K18la modification enhanced the transcriptional activity of NFS1 cysteine desulfurase (NFS1), a key player in iron‒sulfur cluster biosynthesis, thereby reducing the susceptibility of HCC to ferroptosis after IMWA. Knocking down NFS1 diminished the metastatic potential of sublethally heat-treated HCC cells. Additionally, NFS1 deficiency exhibited a synergistic effect with oxaliplatin, leading to the significant inhibition of the metastatic capability of HCC cells both in vitro and in vivo, regardless of sublethal HS treatment. In conclusion, our study revealed the oncogenic role of histone lactylation in HCC after IMVA. We also bridged histone lactylation with ferroptosis, providing novel therapeutic targets for HCC following microwave ablation, particularly when combined with oxaliplatin-based chemotherapy.

Ammonia is the main harmful environmental substance affecting fish culture. The liver is the immune and metabolic organ of fish, and its physiological homeostasis will affect the health of the organism. In this study, healthy golden pompano Trachinotus ovatus juveniles were exposed to 5 mg/L (A5) and 10 mg/L (A10) ammonia-N stress for 7 days and then the variation characteristics of the physiological homeostasis of the liver were analyzed at multiple biological levels. After ammonia stress, the liver showed obvious morphological changes and stress responses. Specifically, the oxidative stress indexes, such as the activities of the anti-superoxide anion generation capacity (ASC) and superoxide dismutase (SOD), were elevated in the A5 and A10 groups, while the glutathione peroxidase (GPx) activity and glutathione (GSH) content were disturbed; the relative expression levels of the Nrf2 and NQO1 genes were increased in the A10 group, while the expressions of the Keap1 and HO1 were decreased in the A5 and A10 groups. Ferroptosis related genes, such as the relative expressions of NOX1, NCOA4, and FPN1 were increased in the A5 and A10 groups, PTGS2 and FTH1 were decreased in the A5 group but elevated in the A10 group, and p53, GPx4, SLC7A11, and NFS1 were only increased in the A10 group. Inflammation related genes, such as TNFα, IL1β, and IL8 relative expression levels, were increased in the A10 group, IL10 was increased in the A5 and A10 groups, while TGFβ was decreased in the A5 group but increased in the A10 group. Immune related genes, such as the expression levels of IgM and IgT, were increased in the A5 group but decreased in the A10 group. The integrated biomarker responses revealed that the hepatotoxicity of ammonia was concentration-dependent, and there was a high correlation between oxidative stress, ferroptosis, inflammation, and immune function changes. These results reveal the hepatotoxicity of ammonia stress on T. ovatus.

Functional RNA plays a crucial role in regulating cellular processes throughout the life cycle of a cell. Identifying functional changes at each stage, from inception to development to maturation, functional execution, and eventual death or pathological transformation, often requires systematic comparisons of functional expression across cell populations. However, because cells of the same type often exhibit similar gene expression patterns regardless of function or fate, it is challenging to distinguish the stages of cellular fate or functional states within the same cell type, which also limits our understanding of cellular memory. Cells of the same type that share structural and gene expression similarities but originate from different regions and perform slightly distinct functions often retain unique epigenetic memory signatures. Although RNA serves as a key executor of fundamental cellular functions, its high expression similarity among cells of the same type limits its ability to distinguish functional heterogeneity. To overcome this challenge, we developed TOGGLE, utilizing higher-resolution analytical methods to uncover functional diversity at the cellular level. Then we based on TOGGLE developed an innovative Graph Diffusion Functional Map, which can significantly reduce noise, thereby more clearly displaying the functional grouping of RNA and enabling the capture of more subtle functional differences in high-dimensional data. Ultimately, this method effectively removes the influence of baseline functions from classification criteria and identifies key trajectories of cell fate determination.

Qizhu Jianwei decoction (QZJWD) is a conventional Chinese medicine formulation used to treat gastric cancer, however, its association with GC and ferroptosis remains poorly understood.

Our research endeavors centered around investigating the potential molecular mechanism of QZJWD in suppressing GC.

A UHPLC-QTOF-MS technique was utilized for determining the major constituents of QZJWD. Laboratory-based experiments such as CCK8, wound healing, transwell invasion assay, and WB were conducted to examine QZJWD's role in influencing HGC-27 and AGS cells, Fe2+, ROS, MDA and GPx levels were assayed to evaluate the activation of ferroptosis. The subcutaneous tumor tissues in nude mice injected with QZJWD were examined. NTA, TEM, and WB served to validate exosomes. To identify the modified miRNAs involved in GC and ferroptosis, sRNA-seq analysis was utilized. Luciferase reporter assay and miRNA mimics transfection experiment were further used validate the specific binding of miRNA and the effect of QZJWD.

QZJWD treatment markedly suppressed the proliferation, migration, and invasion of gastric cancer cells. QZJWD effectively promoted ferroptosis both in vitro and in vivo, by elevating levels of Fe2+, MDA, ROS, and ACSL4 while downregulating GPx levels. Additionally, exosomes originating from QZJWD-treated gastric carcinoma cells were internalized by other gastric carcinoma cells, further amplifying ferroptosis. Notably, QZJWD downregulated exosomal-miR-199-3p, which facilitated ferroptosis in gastric tumor cells through directly targeting ACSL4.

QZJWD may induce ferroptosis through the exosome-mediated miR-199-3p/ACSL4 signaling pathway in gastric cancer. Our research identifies a promising approach for addressing GC in clinical settings.

Irinotecan is a widely used chemotherapy drug in colorectal cancer (CRC). The evolution and prognosis of CRC involve complex mechanisms and depend on the drug administered, especially for irinotecan. However, the specific mechanism and prognostic role of irinotecan-related regulators remain to be elucidated.

Data from public databases were used to explore the multiomic traits of irinotecan-related regulators through bioinformatics analysis. RT‒qPCR, western blotting, transmission electron microscopy and flow cytometry were used as experimental validations.

Iriscore (irinotecan-related score) was constructed based on irinotecan-related regulators, and a high iriscore predicted a poor prognosis, poor therapeutic response and the MSS/MSI-L status. Single-cell analysis revealed that FSTL3 and TMEM98 were mainly expressed in CRC stem cells. Potential transcription factors (E2F1, STAT1, and TTF2) and therapeutic drugs (telatinib) that target irinotecan-related regulators were identified. FSTL3 was the core risk irinotecan-related regulator. Some ferroptosis regulators (GPX4, HSPB1 and RGS4) and related metabolic pathways (lipid oxidation and ROS metabolism) were correlated significantly with FSTL3. In vitro, irinotecan inhibited the expression of FSTL3 and ferroptotic defence proteins (GPX4 and SLC7A11), and induced lipid peroxidation and intracellular Fe (2+) ions concentration increased.

We confirmed that irinotecan-related regulators, especially FSTL3, have effective prognostic value in CRC and speculated that FSTL3 may promote CRC progression and affect ferroptosis, which is beneficial for identifying candidate targeted irinotecan-related regulators and accurate individualized treatment strategies for CRC.

Human cysteine desulfurase (NFS1) participates in numerous critical cellular processes, including iron-sulfur (Fe-S) cluster biosynthesis and tRNA thiolation. NFS1 overexpression has been observed in a variety of cancers, and thus it has been considered a promising anti-tumor therapeutic target. To date, however, no inhibitors targeting NFS1 have been identified. Here, we report the identification of the first potent small-molecule inhibitor (Compound 53, PubChem CID 136847320) of NFS1 through a combination of virtual screening and biological validation. Compound 53 exhibited good selectivity against two other pyridoxal phosphate (PLP)-dependent enzymes. Treatment with Compound 53 inhibited the proliferation of lung cancer (A549) cells (IC50 = 16.3 ± 1.92 μM) and caused an increase in cellular iron levels due to the disruption of Fe-S cluster biogenesis. Furthermore, Compound 53, in combination with 2-AAPA, an inhibitor of glutathione reductase (GR) that elevates cellular reactive oxygen species (ROS) levels, further suppressed the proliferation of A549 cells by triggering ferroptotic cell death. Additionally, the key residues involved in the binding of the inhibitor to the active center of NFS1 were identified through a combination of molecular docking and site-directed mutagenesis. Taken together, we describe the identification of the first selective small-molecule inhibitor of human NFS1.

One of the most prevalent urinary illnesses is kidney stone formation, often known as nephrolithiasis. The precise processes of kidney stone remain poorly known after substantial investigation. In order to successfully prevent and cure stone formation and recurrence, additional research into the pathophysiology of stone formation is of paramount importance. Ferroptosis is linked to a variety of renal diseases and is a critical factor in the death of cells. However, little is known about how ferroptosis-related genes (FRGs) contribute to the development of kidney stones.

The Ferroptosis Database and the Gene Expression Omnibus (GEO) database provided us with information on kidney stones and FRGs, respectively (FerrDb).

Eight DE-FRGs related to kidney stones were found in total, and they were all closely related to immune response and autophagy management. Following this, among the 8 DE-FRGs, LASSO and SVM-RFE algorithms chose FZD7, STK11, SUV39H1, and LCN2 as marker genes with suitable diagnostic capabilities. These marker genes may be involved in the control of the PPAR signaling pathway, mTOR signaling system, and fatty acid production of kidney stones, according to the functional enrichment analysis that followed. Additionally, 24 drugs that target two marker genes have been found. Despite this, the ceRNA networks have gained that the regulatory relationship between marker genes is rather complex. Additionally, the findings of the CIBERSORT investigation indicated that FZD7 and SUV39H1 may be linked to variations in the immune milieu of people who have kidney stones.

We developed a diagnostic tool and provided information on the development of kidney stones. In order to confirm its diagnostic applicability for kidney stones, more studies are needed before it may be used in clinical practice.

Mitochondrial functionality and cellular iron homeostasis are closely intertwined. Mitochondria are biosynthetic hubs for essential iron cofactors such as iron-sulfur (Fe-S) clusters and heme. These cofactors, in turn, enable key mitochondrial pathways, such as energy and metabolite production. Mishandling of mitochondrial iron is associated with a spectrum of human pathologies ranging from rare genetic disorders to common conditions. Here, we review mitochondrial iron utilization and its intersection with disease.

Osteoporosis (OP) is a common disease in the elderly, characterized by decreased bone strength, reduced bone density, and increased fracture risk. There are two clinical types of osteoporosis: primary osteoporosis and secondary osteoporosis. The most common form is postmenopausal osteoporosis, which is caused by decreased estrogen production after menopause. Secondary osteoporosis, on the other hand, occurs when certain medications, diabetes, or nutritional deficiencies lead to a decrease in bone density. Ferroptosis, a new iron-dependent programmed cell death process, is critical in regulating the development of osteoporosis, but the underlying molecular mechanisms are complex. In the pathologic process of osteoporosis, several studies have found that ferroptosis may occur in osteocytes, osteoblasts, and osteoclasts, cell types closely related to bone metabolism. The imbalance of iron homeostasis in osteoblasts and excessive iron accumulation can promote lipid peroxidation through the Fenton reaction, which induces ferroptosis in osteoblasts and affects their role in regulating bone metabolism. Ferroptosis in osteoblasts inhibits bone formation and reduces the amount of new bone production. Osteoclast-associated ferroptosis abnormalities, on the other hand, may alter the homeostasis of bone resorption. In this paper, we start from the molecular mechanism of ferroptosis, and introduce the ways in which ferroptosis affects the physiological and pathological processes of the body. After that, the effects of ferroptosis on osteoblasts and osteoclasts will be discussed separately to elucidate the molecular mechanism between ferroptosis and osteoporosis, which will provide a new breakthrough for the prevention and treatment of osteoporosis and a more effective and better idea for the treatment strategy of osteoporosis.

Photosensitizers (PSs) featuring type I reactive oxygen species (ROS) generation and aggregation-induced emission (AIE) activity offer a promising solution to achieve non-invasive and precise theranostics. However, the reported AIE luminogens (AIEgens) with both AIE characteristic and strong type-I ROS generation are still scarce and the structure-property relationship is still unclear. Herein, an innovative acceptor elongation boosted intersystem crossing (AEBIC) design strategy has been proposed to endow the AIEgen strong type-I ROS producibility. The results indicate that the obtained AIEgen exhibit type-I ROS and aggregation-enhanced ROS efficacy, which has been verified by both experimental and theoretical results. Mechanistic study reveal that the acceptor elongation has promoted a dual-channel intersystem crossing pathway to enhance the intersystem crossing (ISC) process due to the differences in triplet configurations, which can be further amplified by aggregation. The afforded type-I AIE-PS show lipid droplet-anchored characteristic and can induce the ferroptosis through destroying the cellular redox homeostasis and increasing lethal levels of lipid peroxidation. Finally, targeting ferroptosis-based cancer therapy can be realized with excellent anti-tumor effect.

The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.

Ferroptosis, an iron-dependent form of cell death, has been the focus of extensive research over the past decade, leading to the elucidation of key molecules and mechanisms involved in this process. While several studies have highlighted iron sources for the Fenton reaction, the predominant mechanism for iron release in ferroptosis has been identified as ferritinophagy, which occurs in response to iron starvation. However, much of the existing literature has concentrated on lipid peroxidation rather than on the mechanisms of iron release. This review proposes three distinct mechanisms of iron mobilization: ferritinophagy, reductive pathways with selective gating of ferritin pores, and quinone-mediated iron mobilization. Notably, the latter two mechanisms operate independently of iron starvation and rely primarily on reductants such as NADH and O2•-. The inhibition of the respiratory chain, particularly under the activation of α-ketoglutarate dehydrogenase, leads to the accumulation of these reductants, which in turn promotes iron release from ferritin and indirectly inhibits AMP-activated protein kinase through excessive iron levels. In this work, we delineate the intricate relationship between iron mobilization and bioenergetic processes under conditions of oxidative stress. Furthermore, this review aims to enhance the understanding of the connections between ferroptosis and these mechanisms.

Ferroptosis is an iron-dependent nonapoptotic regulated cell death modality characterized by lethal levels of lipid peroxide accumulation and disrupted antioxidant systems. An increasing number of studies have revealed correlations between ferroptosis and the pathophysiology and treatment of cancer. Given the intricate involvement of mitochondria in ferroptosis, as suggested by previous studies, here, we review advances in understanding the roles of mitochondrial quality control and mitochondrial metabolism (including the roles of the TCA cycle, reactive oxygen species, iron metabolism, and lipid metabolism) in cancer-related ferroptosis and outline the molecular mechanism and clinical translation of mitochondria-related ferroptosis in cancer treatment. with the aim of promoting the precise utilization and prevention of ferroptosis in cancer therapeutics.

Intervertebral disc degeneration (IDD) is intricately linked to the pathogenesis of low back pain (LBP). The balance of nucleus pulposus (NP) cell and intervertebral disc (IVD) integrity is significantly supported by amino acid metabolism within an avascular milieu. However, the specific metabolic demands during the progression of IDD are not fully understood. Our study revealed that GLS1, a key enzyme that regulates glutamine metabolism, is key for mitigating NP cell ferroptosis, senescence, and IDD progression. Our findings show that GLS1 overexpression modulates glutamine metabolism, reducing NP cell matrix degradation, ferroptosis, and senescence. Mechanistically, GLS1 interacts with NFS1 and regulates ferrous ion (Fe2+) homeostasis. GLS1-driven glutamine metabolism facilitates acetyl-CoA production, which is important for the histone acetylation of NFS1. Thus, restoring GLS1 activity through gene overexpression to maintain Fe2+ homeostasis is a promising approach for mitigating matrix degradation, ferroptosis, and senescence and for rejuvenating intervertebral discs. Collectively, our data suggest a model in which GLS1-mediated glutamine metabolism is associated with NP cell matrix degradation, ferroptosis, and senescence and that NFS1 can be targeted to maintain Fe2+ homeostasis and ultimately revitalize intervertebral discs.

Maintaining iron homeostasis is necessary for kidney functioning. There is more and more research indicating that kidney disease is often caused by iron imbalance. Over the past decade, ferroptosis' role in mediating the development and progression of renal disorders, such as acute kidney injury (renal ischemia-reperfusion injury, drug-induced acute kidney injury, severe acute pancreatitis induced acute kidney injury and sepsis-associated acute kidney injury), chronic kidney disease (diabetic nephropathy, renal fibrosis, autosomal dominant polycystic kidney disease) and renal cell carcinoma, has come into focus. Thus, knowing kidney iron metabolism and ferroptosis regulation may enhance disease therapy. In this review, we discuss the metabolic and molecular mechanisms of iron signaling and ferroptosis in kidney disease. We also explore the possible targets of ferroptosis in the therapy of renal illness, as well as their existing limitations and future strategies.

Despite advances in the management of head and neck squamous cell carcinoma (HNSCC), prognostic models and treatment strategies remain inadequate, particularly for HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). The rising incidence of HPV-positive OPSCC highlights an urgent need for innovative therapeutic approaches. Ferroptosis, a regulated form of non-apoptotic cell death, has gained attention for its role in cancer progression, but its potential as a prognostic and therapeutic target in HPV-positive OPSCC remains largely unexplored. This study investigates the role of ferroptosis in HPV-positive OPSCC, aiming to identify prognostic markers and provide insights into potential therapeutic strategies that could improve patient outcomes.

Thirteen ferroptosis gene expression signatures were retrieved from the literature, and their performance and association to the immune microenvironment were validated on a meta-analysis of 267 HPV-positive cases (Metanalysis-HPV267) and 286 samples from the BD2Decide project (BD2-HPV286).

Our analysis revealed that specific ferroptosis-related gene expression signatures, particularly FER3, FER4, FER6, and FER12, are significantly associated (p-value < 0.05) with high-risk patient groups and adverse tumor microenvironment features, including suppressed immune activity and enhanced stromal involvement. Elevated expression of CAV1, a ferroptosis suppressor, further delineates high-risk profiles.

These findings highlight the prognostic significance of ferroptosis in stratifying patients and identifying those with poorer clinical outcomes. Targeting ferroptosis pathways represents a novel and promising approach to addressing the unmet need for effective prognostic and therapeutic strategies in HPV-positive OPSCC. Future research should focus on translating these findings into clinical applications to advance precision oncology and improve outcomes for this growing patient population.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with poorly understood underlying molecular mechanisms. Ferroptosis, a form of programmed cell death, is not fully elucidated in NPC.

We conducted quantitative proteomics to detect dysregulated proteins in NPC tissues. The levels of endoplasmic reticulum membrane protein complex 2 (EMC2) in NPC tissue microarrays were evaluated by immunohistochemistry, and the prognostic value of EMC2 was analyzed in NPC patients. The role of EMC2 in ferroptosis and carcinogenesis was determined through in vitro and in vivo experiments. Quantitative proteomics, protease inhibition, ubiquitin detection, and rescue experiments were performed to explore the mechanism of EMC2-regulated ferroptosis.

Significantly upregulated EMC2 was detected in NPC, and it was closely related to the characteristics of tumor progression. Elevated EMC2 was obviously correlated with poor survival in patients with NPC. EMC2 knockdown promoted ferroptosis, inhibiting cell viability, migration, and invasion, and enhancing the efficacy of cisplatin in NPC cells. Conversely, EMC2 overexpression contributed to ferroptosis repression, malignant progression, and reduced the efficacy of cisplatin. In addition, EMC2 knockdown suppressed xenograft tumor growth and enhanced ferroptosis in nude mice. Mechanistically, we identified transferrin receptor (TFRC) as a critical downstream protein. EMC2 interacted with TFRC and promoted its ubiquitin-proteasomal degradation. EMC2 regulated ferroptosis by mediating the level of TFRC.

EMC2 suppresses ferroptosis and promotes tumor progression, and the EMC2-TFRC axis is a novel ferroptosis regulatory pathway. EMC2 is a potentially biomarker and therapeutic target for NPC.

Ferroptosis is a regulated cell death mechanism distinct from apoptosis, autophagy, and necroptosis, marked by iron accumulation and lipid peroxidation. Since its identification in 2012, it has developed into a potential therapeutic target, especially concerning GI disorders like PC, HCC, GC, and CRC. This interest arises from the distinctive role of ferroptosis in the progression of diseases, presenting a new avenue for treatment where existing therapies fall short. Recent studies emphasize the promise of focusing on ferroptosis to fight GI cancers, showcasing its unique pathophysiological mechanisms compared to other types of cell death. By comprehending how ferroptosis aids in the onset and advancement of GI diseases, scientists aim to discover novel drug targets and treatment approaches. Investigating ferroptosis in gastrointestinal disorders reveals exciting possibilities for novel therapies, potentially revolutionizing cancer treatment and providing renewed hope for individuals affected by these tumors.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is rising in global incidence and mortality. Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disease, is strongly linked to metabolic conditions that can progress to liver cirrhosis and HCC. Iron overload (IO), whether inherited or acquired, results in abnormal iron hepatic deposition, significantly impacting MASLD development and progression to HCC. While the pathophysiological connections between hepatic IO, MASLD, and HCC are not fully understood, dysregulation of glucose and lipid metabolism and IO-induced oxidative stress are being investigated as the primary drivers. Genomic analyses of inherited IO conditions reveal inconsistencies in the association of certain mutations with liver malignancies. Moreover, hepatic IO is also associated with hepcidin dysregulation and activation of ferroptosis, representing promising targets for HCC risk assessment and therapeutic intervention. Understanding the relationship between hepatic IO, MASLD, and HCC is essential for advancing clinical strategies against liver disease progression, particularly with recent IO-targeted therapies showing potential at improving liver biochemistry and insulin sensitivity. In this review, we summarize the current evidence on the pathophysiological association between hepatic IO and the progression of MASLD to HCC, underscoring the importance of early diagnosis, risk stratification, and targeted treatment for these interconnected conditions.

Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation. This process is regulated by signaling pathways associated with redox balance, iron metabolism, and lipid metabolism. Cancer cells' increased iron demand makes them especially susceptible to ferroptosis, significantly influencing cancer development, therapeutic response, and metastasis. Recent findings indicate that cancer cells can evade ferroptosis by downregulating key signaling pathways related to this process, contributing to drug resistance. This underscores the possibility of modulating ferroptosis as an approach to counteract drug resistance and enhance therapeutic efficacy. This review outlines the signaling pathways involved in ferroptosis and their interactions with cancer-related signaling pathways. We also highlight the current understanding of ferroptosis in cancer drug resistance, offering insights into how targeting ferroptosis can provide novel therapeutic approaches for drug-resistant cancers. Finally, we explore the potential of ferroptosis-inducing compounds and examine the challenges and opportunities for drug development in this evolving field.

Sanggenon c, a component in Morus alba L, has been proved to possess various biological activities. The aim of this study is to investigate whether sanggenon c can target SLC7A11 and inhibit lung cancer by regulating the ferroptosis mechanism. The levels of antioxidant factor, Fe 2+, and SLC7A11 were measured in the lungs of cancerous mice and human A 549 lung cancer cells. The computer-aided techniques were employed to validate the molecular docking and molecular dynamics simulations of sanggenon c and SLC7A11. The sanggenon c significantly inhibits lung cancer cell metastasis in vivo and A 549 cell proliferation in vitro by targeting the over-expression of SLC7A11, which inhibits GPX 4 and induces the release of ROS and MDA, effectively triggering ferroptosis. The interaction between sanggenon c and SLC7A11 exhibits a strong binding affinity, leading to the significant inhibition of the key protein SLC7A11. This restriction of system xc- transport induces ferroptosis in lung cancer. It epitomizes a groundbreaking inhibitor specifically designed to target SLC7A11.

Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 in enhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.

Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.