Form Of Regulated Cell Death Research Articles

Using Label-Free Raman Spectroscopy Integrated with Microfluidic Chips to Probe Ferroptosis Networks in Cells.

Ferroptosis, a regulated form of cell death driven by oxidative stress and lipid peroxidation, has emerged as a pivotal research focus with implications across various cellular contexts. In this study, we employed a multifaceted approach, integrating label-free Raman spectroscopy and microfluidics to study the mechanisms underpinning ferroptosis. Our investigations included the ferroptosis initiation based on the changes in the lipid Raman band at 1436 cm-1 under different cellular states, the generation of reactive oxygen species (ROS), lipid peroxidation, DNA damage/repair, and mitochondrial dysfunction. Importantly, our work highlighted the dynamic role of vital cellular components, such as nicotinamide adenine dinucleotide phosphate hydrogen (NADPH), ferredoxin clusters, and other key factors such as glutathione peroxidase 4 and nuclear factor erythroid 2, which collectively influenced cellular responses to redox imbalance and oxidative stress. Quantum mechanical (QM) and molecular docking simulations (MD) provided further evidence of interactions between the ferredoxin (containing 4Fe-4S clusters), NADPH, and ROS, which led to the production of reactive Fe species in the cells. As such, our approach not only offered a real-time, multidimensional perspective on ferroptosis but also provided valuable methods and insights for therapeutic interventions in diverse biomedical contexts.

Research progress of ferroptosis in brain injury

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, has emerged as a key contributor to neuronal damage in various types of brain injury, including traumatic brain injury (TBI) and ischemic brain injury caused by brian ischemia (BI). This review summarizes the underlying mechanisms of ferroptosis in brain injuries and highlights its role in exacerbating neuronal loss, inflammation, and secondary damage. After TBI, the release of free iron and oxidative stress after injury triggers ferroptosis, contributing to long-term neurological deficits. Similarly, in BI, ferroptosis is initiated by the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction during ischemia and reperfusion, further amplifying neuronal damage. The current review provides a comprehensive overview of the interplay between ferroptosis and brain injury, with an emphasis on the potential of targeting ferroptosis to improve recovery outcomes in patients. Future research directions include the development of novel ferroptosis inhibitors and the integration of ferroptosis-targeting strategies with existing treatment modalities.

Crosstalk between non-coding RNA and apoptotic signaling in diabetic nephropathy.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in diabetes mellitus. It is also a significant contributor to cardiovascular morbidity and mortality in diabetic patients Thereby, Innovative therapeutic approaches are needed to retard the initiation and advancement of DN. Hyperglycemia can induce apoptosis, a regulated form of cell death, in multiple renal cell types, such as podocytes, mesangial cells, and proximal tubule epithelial cells, ultimately contributing to the pathogenesis of DN. Recent genome-wide investigations have revealed the widespread transcription of the human genome, resulting in the production of numerous regulatory non-protein-coding RNAs (ncRNAs), including microRNAs (miRNAs) and diverse categories of long non-coding RNAs (lncRNAs). They play a critical role in preserving physiological homeostasis, while their dysregulation has been implicated in a broad spectrum of disorders, including DN. Considering the established association between apoptotic processes and the expression of ncRNAs in DN, a thorough understanding of their intricate interplay is essential. Therefore, the current work thoroughly analyzes the intricate interplay among miRNAs, lncRNAs, and circular RNAs in the context of apoptosis within the pathogenesis of DN. Additionally, in the final section, we demonstrated that ncRNA-mediated modulation of apoptosis can be achieved through stem cell-derived exosomes and herbal medicines, presenting potential avenues for the treatment of DN.

Inhibition of an Alzheimer's disease-associated form of necroptosis rescues neuronal death in mouse models.

Necroptosis is a regulated form of cell death that has been observed in Alzheimer's disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)-Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as "GVD-necroptosis" may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD.

Inducing disulfidptosis in tumors:potential pathways and significance.

Regulated cell death (RCD) is crucial for the elimination of abnormal cells. In recent years, strategies aimed at inducing RCD, particularly apoptosis, have become increasingly important in cancer therapy. However, the ability of tumor cells to evade apoptosis has led to treatment resistance and relapse, prompting extensive research into alternative death processes in cancer cells. A recent study identified a novel form of RCD known as disulfidptosis, which is linked to disulfide stress. Cancer cells import cystine from the extracellular environment via solute carrier family 7 member 11 (SLC7A11) and convert it to cysteine using nicotinamide adenine dinucleotide phosphate (NADPH). When NADPH is deficient or its utilization is impaired, cystine accumulates, leading to the formation of disulfide bonds in the actin cytoskeleton, triggering disulfidptosis. Disulfidptosis reveals a metabolic vulnerability in tumors, offering new insights into cancer therapy strategies. This review provides a detailed overview of the mechanisms underlying disulfidptosis, the current research progress, and limitations. It also highlights innovative strategies for inducing disulfidptosis and explores the potential of combining these approaches with traditional cancer therapies, particularly immunotherapy, to expedite clinical translation.

Raloxifene Prevents Chemically-Induced Ferroptotic Neuronal Death In Vitro and In Vivo.

Ferroptosis, a regulated form of cell death characterized by excessive iron-dependent lipid peroxidation, can be readily induced in cultured cells by chemicals such as erastin and RSL3. Protein disulfide isomerase (PDI) has been identified as an upstream mediator of chemically induced ferroptosis and also a target for ferroptosis protection. In this study, we discovered that raloxifene (RAL), a selective estrogen receptor modulator known for its neuroprotective actions in humans, can effectively inhibit PDI function and provide robust protection against chemically induced ferroptosis in cultured HT22 neuronal cells. Specifically, RAL can bind directly to PDI both in vitro and in intact neuronal cells and inhibit its catalytic activity. Computational modeling analysis reveals that RAL can tightly bind to PDI through forming a hydrogen bond with its His256 residue, and biochemical analysis further shows that when PDI's His256 is mutated to Ala256, RAL loses its inhibition of PDI's catalytic activity. This inhibition of PDI by RAL significantly reduces the dimerization of both the inducible and neuronal nitric oxide synthases and the accumulation of nitric oxide, both of which have recently been shown to play a crucial role in mediating chemically induced ferroptosis through subsequent induction of ROS and lipid-ROS accumulation. In vivo behavioral analysis shows that mice treated with RAL are strongly protected against kainic acid-induced memory deficits and hippocampal neuronal damage. In conclusion, this study demonstrates that RAL is a potent inhibitor of PDI and can effectively prevent chemically induced ferroptosis in hippocampal neurons both in vitro and in vivo. These findings offer a novel estrogen receptor-independent mechanism for RAL's neuroprotective actions in animal models and humans.

Squalene monooxygenase (SQLE) protects ovarian cancer cells from ferroptosis.

Altered cholesterol metabolism has been linked to a poor prognosis in various types of cancer. Cholesterol oxidation can lead to lipid peroxidation, membrane damage, and cell death. Ferroptosis is a regulated form of cell death characterized by the accumulation of lipid peroxides, which significantly inhibits the growth of ovarian cancer cells. SQLE is the primary enzyme responsible for catalyzing cholesterol lipid synthesis and is notably expressed in ovarian cancer tissues and cells. This study aims to investigate the role of squalene monooxygenase (SQLE) in ferroptosis in ovarian cancer. The protein and mRNA expression of SQLE was assessed using qRT-PCR, Western Blot, and immunohistochemistry. The association between SQLE and ferroptosis was demonstrated through analysis of TCGA and GTEx databases, TMT protein sequencing, as well as validation by qRT-PCR, Western Blot, immunofluorescence, ROS detection, and lipid peroxide detection. Animal experiments further confirmed the relationship between SQLE and ferroptosis in ovarian cancer. The protein and mRNA expression of SQLE was found to be upregulated in both ovarian cancer tissues and cell lines. Decreased SQLE expression led to ferroptosis in ovarian cancer cells, thereby increasing their sensitivity to ferroptosis inducers. Our research demonstrates that SQLE is significantly upregulated in both ovarian cancer tissues and cells. The overexpression of SQLE in ovarian cancer may facilitate tumorigenesis by conferring resistance to ferroptosis, thus shedding light on potential novel therapeutic strategies for ovarian cancer.

NRF2 inhibits RSL3 induced ferroptosis in gastric cancer through regulation of AKR1B1

Gastric cancer is a malignant tumor associated with a high mortality rate. Recently, emerging evidence has shown that ferroptosis, a regulated form of cell death induced by iron (Fe)-dependent lipid peroxidation. Nuclear factor E2 related factor 2 (NRF2) is a key regulator of intracellular oxidation homeostasis that plays a pivotal role in controlling lipid peroxidation, which is closely related to the process of ferroptosis. However, the molecular mechanism of NRF2 on ferroptosis remains to be investigated in gastric cancer. In our study, NRF 2 was found to transcriptionally activate Aldo-keto reductase 1 member B1 (AKR1B1) expression in gastric cancer. AKR1B1 is involved in the regulation of lipid metabolism by removing the aldehyde group of glutathione. We found that AKR1B1 is highly expressed in gastric cancer and is associated with a poor prognosis of the patients. In vitro experiments found that AKR1B1 has the ability to promote the proliferation and invasion of gastric cancer cells. AKR1B1 inhibited RSL3-induced ferroptosis in gastric cancer by reducing reactive oxygen species accumulation and lipid peroxidation, as well as decreasing intracellular ferrous ion and malondialdehyde expression and increasing glutathione expression. Our study demonstrated that AKR1B1 resisted RSL3-induced ferroptosis by regulating GPX4, PTGS2 and ACSL4, which was further demonstrated in a xenograft nude mouse model. Our work reveals a critical role for the AKR1B1 in the resistance to RSL3-induced ferroptosis in gastric cancer.

Uncovering the role of RPL8 in glutathione synthesis-dependent ferroptosis control in hepatocellular carcinoma

IntroductionHepatocellular carcinoma (HCC) is profoundly affected by ferroptosis, a regulated form of cell death associated with iron metabolism and oxidative stress, which is regulated by glutathione (GSH) levels. Influence. This study explored the role of ferroptosis-related genes (FRG) in HCC and evaluated the impact of RPL8 on HCC progression and ferroptosis mechanisms.Material and methodsThrough comprehensive TCGA-LIHC data analysis, we identified significant FRGs affecting HCC prognosis. The expression and functional significance of RPL8 in HCC were further evaluated using cell line models and tumor xenograft experiments, focusing on its effects on cell proliferation, invasion, migration, apoptosis, and regulation of ferroptosis.ResultsElevated RPL8 expression was observed in HCC tissues and cell lines. Functional experimental results showed that RPL8 regulation significantly affects cell proliferation, invasion, migration, and apoptosis. RPL8 silencing significantly inhibited tumor growth in tumor xenograft experiments. Furthermore, RPL8 knockdown resulted in increased 4-HNE levels, indicating increased lipid peroxidation and triggering ferroptosis, which was partially alleviated by inhibitors such as Nec-1, Z-VAD-FMK, and Fer-1. RPL8 was also found to significantly alter the production of glycine, glutamate, and cysteine, upregulate glutathione synthase (GSS) protein levels, and enhance the GSH synthesis pathway.ConclusionsRPL8 plays a key role in regulating HCC ferroptosis and tumor progression, affecting cellular defense by regulating GSH synthesis. These insights highlight RPL8 as a promising target for therapeutic intervention in HCC.

Inhibition of FSP1: A new strategy for the treatment of tumors (Review).

Ferroptosis, a regulated form of cell death, is intricately linked to iron‑dependent lipid peroxidation. Recent evidence strongly supports the induction of ferroptosis as a promising strategy for treating cancers resistant to conventional therapies. A key player in ferroptosis regulation is ferroptosis suppressor protein 1 (FSP1), which promotes cancer cell resistance by promoting the production of the antioxidant form of coenzyme Q10. Of note, FSP1 confers resistance to ferroptosis independently of the glutathione (GSH) and glutathione peroxidase‑4 pathway. Therefore, targeting FSP1 to weaken its inhibition of ferroptosis may be a viable strategy for treating refractory cancer. This review aims to clarify the molecular mechanisms underlying ferroptosis, the specific pathway by which FSP1 suppresses ferroptosis and the effect of FSP1 inhibitors on cancer cells.

The emerging roles of necroptosis in skeletal muscle health and disease.

Necroptosis is a regulated form of cell death with implications in various physiological and pathological processes in multiple tissues. However, the relevant findings from post-mitotic tissues, such as skeletal muscle, are scarce. This review summarizes the potential contributions of necroptosis to skeletal muscle health and diseases. It first discusses the physiological roles of necroptosis in muscle regeneration and development. It then summarizes the contributions of necroptosis to the pathogenesis of multiple muscle diseases, including muscular dystrophies, inflammatory myopathies, cachexia, and neuromuscular disorders. Lastly, it unravels the gaps in our understanding and therapeutic challenges of inhibiting necroptosis as a potential intervention for muscle diseases. Specifically, the findings from the transgenic animal models and the use of pharmacological inhibitors of necroptosis are discussed with relevance to improving the structure and/or function of skeletal muscle in various diseases. Recent developments from experimental animal models and clinical data are presented to discuss the roles of necroptosis in skeletal muscle health and diseases.

SQSTM1 improves acute lung injury via inhibiting airway epithelium ferroptosis in a vitamin D receptor/autophagy-mediated manner

Emerging evidence has reported that acute lung injury (ALI), characterized by inflammation and oxidative stress in airway epithelium, is regulated by programmed cell death. Ferroptosis, a regulated form of cell death spurred by uncontrolled lipid peroxidation, has been proven to implicate various diseases. Inhibiting ferroptosis represents a feasible strategy for ALI through the suppression of lipid peroxidation, while the mechanism remains to be further elucidated. Here, we identified Sequestosome 1 (SQSTM1) as a negative regulator of airway epithelium ferroptosis during ALI. SQSTM1 knockdown cells manifested higher sensitivity to ferroptosis. Mechanistically, SQSTM1 was found to directly interact with vitamin D receptor (VDR) through its nuclear receptor (NR) box motif, facilitating its nuclear translocation and initiating autophagy at the transcriptional level. To further validate these findings, an in vivo preventive model utilizing spermidine, a proven inducer of SQSTM1 was established. The results consistently demonstrated that spermidine supplementation significantly induced SQSTM1 and ameliorated ALI by mitigating airway epithelial ferroptosis. Notably, these effects were abrogated in the absence of SQSTM1. Taken together, this study identified SQSTM1 as a negative regulator of airway epithelium ferroptosis in a VDR-mediated autophagy manner, making it a potential therapeutic target for the treatment of ALI.

Molecular and therapeutic landscape of ferroptosis in skin diseases.

Regulated cell death (RCD) is a critical physiological process essential in maintaining skin homeostasis. Among the various forms of RCD, ferroptosis stands out due to its distinct features of iron accumulation, lipid peroxidation, and involvement of various inhibitory antioxidant systems. In recent years, an expanding body of research has solidly linked ferroptosis to the emergence of skin disorders. Therefore, understanding the mechanisms underlying ferroptosis in skin diseases is crucial for advancing therapy and prevention strategies. This review commences with a succinct elucidation of the mechanisms that underpin ferroptosis, embarks on a thorough exploration of ferroptosis's role across a spectrum of skin conditions, encompassing melanoma, psoriasis, systemic lupus erythematosus (SLE), vitiligo, and dermatological ailments precipitated by ultraviolet (UV) exposure, and scrutinizes the potential therapeutic benefits of pharmacological interventions aimed at modulating ferroptosis for the amelioration of skin diseases.

Research Progress on Ferroptosis and Nanotechnology-Based Treatment in Triple-Negative Breast Cancer.

In recent years, more and more researches on cell death mode in breast cancer, including apoptosis, ferroptosis, etc. Ferroptosisis a regulated form of cell death characterized by iron-dependent accumulation of lipid peroxidation to lethal levels, and numerous studies have shown that ferroptosis is closely associated with tumor cells. Breast cancer is one of the malignant tumors with the highest incidence in women, and TNBC accounts for about 15-20% of all types of breast cancer. Due to the poor prognosis, strong aggressiveness, high drug resistance and lack of molecular targeting characteristics of TNBC, the treatment of TNBC faces many difficulties and great challenges. A large number of studies have shown that ferroptosis plays an important role in the occurrence and development of TNBC, tumor diagnosis, treatment and prognosis, among which the main mechanisms inducing ferroptosis include oxidative stress pathway, iron metabolism pathway and lipid metabolism pathway. Since TNBC is highly sensitive to oxidative stress pathways, intracellular GSH reduces reactive oxygen species under the action of GSH peroxidase (GPX), and when intracellular lipid peroxidase (LPO) accumulates to a certain level, ferroptosis will be induced, thus achieving the purpose of killing TNBC cells. In addition, lipid metabolism is highly consistent with the high lipid level of TNBC tumor cells. As a new therapeutic method, nanotechnology has added security to the treatment of cancer with its high safety and excellent biocompatibility. Therefore, the combination of nanotechnology with iron-based radiotherapy, chemotherapy, targeting and immunization has great research value for the treatment of TNBC In addition, the novel idea of treating TNBC with ethnopharmacology combined with ferroptosis is also involved. This article reviews the mechanism of ferroptosis and the recent research on the treatment prospects of TNBC based on ferroptosis and nanotechnology, hoping to provide references for the treatment of diseases based on ferroptosis.

Potential Role of Herbal Remedies on Mesenchymal Stem Cells: An Overview of New Therapeutic Strategies for Osteoporosis

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical mechanism in cancer biology. Understanding the molecular mechanisms and experimental models of ferroptosis is essential for developing novel therapeutic strategies. Organoid models, which closely mimic the architecture and functionality of human tissues, offer a promising platform for studying ferroptosis in various cancer types. This review explores the construction and application of organoid models, highlighting their advantages in cancer research. We discuss the link between ferroptosis and organoids in various cancers, including colorectal cancer, pancreatic cancer, liver cancer, breast cancer, gastric cancer, ovarian cancer, and other cancers. Furthermore, we examine the therapeutic implications of ferroptosis in organoid models, emphasizing the potential for these models to enhance our understanding of cancer biology and improve treatment outcomes.

Identifying and evaluating a disulfidptosis-related gene signature to predict prognosis in colorectal adenocarcinoma patients.

Disulfidptosis, a regulated form of cell death, has been recently reported in cancers characterized by high SLC7A11 expression, including invasive breast carcinoma, lung adenocarcinoma, and hepatocellular carcinoma. However, its role in colon adenocarcinoma (COAD) has been infrequently discussed. In this study, we developed and validated a prognostic model based on 20 disulfidptosis-related genes (DRGs) using LASSO and Cox regression analyses. The robustness and practicality of this model were assessed via a nomogram. Subsequent correlation and enrichment analysis revealed a relationship between the risk score, several critical cancer-related biological processes, immune cell infiltration, and the expression of oncogenes and cell senescence-related genes. POU4F1, a significant component of our model, might function as an oncogene due to its upregulation in COAD tumors and its positive correlation with oncogene expression. In vitro assays demonstrated that POU4F1 knockdown noticeably decreased cell proliferation and migration but increased cell senescence in COAD cells. We further investigated the regulatory role of the DRG in disulfidptosis by culturing cells in a glucose-deprived medium. In summary, our research revealed and confirmed a DRG-based risk prediction model for COAD patients and verified the role of POU4F1 in promoting cell proliferation, migration, and disulfidptosis.

MLKL, a new actor of UVB-induced apoptosis in human diploid dermal fibroblasts

Ultraviolet radiation (UVR) is a major environmental mutagen. In skin, UVR can initiate cancer through the induction of mutagenic DNA damage and promote its progression. An important cancer prevention mechanism is the regulated cell death (RCD), which can safely dispose of damaged cells. Apoptosis, a well-known RCD, is known to be activated by UVR, but part of the mechanism and proteins involved in UVR-induced apoptosis are still to be discovered. Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) are two proteins involved in necroptosis, a form of RCD. Here, we have evaluated the implication of RIPK3 and MLKL in UVB-induced cell death in human diploid dermal fibroblasts. Our results show that RIPK3 and MLKL play opposite roles in UVB-induced cell death, in a necroptosis independent pathway. We showed that RIPK3 protects cells from UVB cell death, while MLKL sensitizes cells to UVB-induced apoptosis. Taken together these results are the first to show the implication of RIPK3 and MLKL in survival and apoptosis, respectively, bringing two new actors in UVB-induced cell death pathway.

Mechanisms of Ferroptosis-Related Genes in Gallbladder Cancer Based on Bioinformatics Analysis.

Gallbladder Cancer (GBC) is a lethal malignancy with limited treatment options and poor prognosis. Recent studies have emphasized the role of ferroptosis, a regulated form of cell death, in various cancers, including GBC. We applied bioinformatics methodologies on four GBC datasets to identify differentially expressed genes (DEGs). An intersection of DEGs from the four datasets with ferroptosis and GBC-associated genes was done to identify key ferroptosis-related genes in GBC. GSVA pathway enrichment analysis and immune cell infiltration assessment were conducted to explore their functional roles and interactions. Seven ferroptosis-related genes, EZH2, MUC1, PVT1, GOT1, CDO1, LIFR, and TFAP2A, were identified to be related to GBC. These genes were associated with vital signaling pathways like the G2/M checkpoint and DNA repair and showed significant correlations with immune cell infiltration in GBC. Receiver Operating Characteristic (ROC) curve analysis revealed their high diagnostic potential, with Area Under the Curve (AUC) values ranging from 0.796 to 0.953. Our findings underscore the pivotal role of ferroptosis in GBC and the potential of ferroptosis-related genes as diagnostic biomarkers. This study lays a foundation for further research into ferroptosis-based therapeutic strategies for GBC.

Identifying an immunogenic cell death-related gene signature contributes to predicting prognosis, immunotherapy efficacy, and tumor microenvironment of lung adenocarcinoma.

Immunogenic cell death (ICD) is a regulated form of cell death that triggers an adaptive immune response. The objective of this study was to investigate the correlation between ICD-related genes (ICDGs) and the prognosis and the immune microenvironment of patients with lung adenocarcinoma (LUAD). ICD-associated molecular subtypes were identified through consensus clustering. Subsequently, a prognostic risk model comprising 5 ICDGs was constructed using Lasso-Cox regression in the TCGA training cohort and further tested in the GEO cohort. Enriched pathways among the subtypes were analyzed using GO, KEGG, and GSVA. Furthermore, the immune microenvironment was assessed using ESTIMATE, CIBERSORT, and ssGSEA analyses. Consensus clustering divided LUAD patients into three ICDG subtypes with significant differences in prognosis and the immune microenvironment. A prognostic risk model was constructed based on 5 ICDGs and it was used to classify the patients into two risk groups; the high-risk group had poorer prognosis and an immunosuppressive microenvironment characterized by low immune score, low immune status, high abundance of immunosuppressive cells, and high expression of tumor purity. Cox regression, ROC curve analysis, and a nomogram indicated that the risk model was an independent prognostic factor. The five hub genes were verified by TCGA database, cell sublocalization immunofluorescence analysis, IHC images and qRT-PCR, which were consistent with bioinformatics analysis. The molecular subtypes and a risk model based on ICDGs proposed in our study are both promising prognostic classifications in LUAD, which may provide novel insights for developing accurate targeted cancer therapies.

Increased Vulnerability to Ferroptosis in FUS-ALS.

Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation, plays a pivotal role in various pathological conditions, including neurodegenerative diseases. While reasonable evidence for ferroptosis exists, e.g., in Parkinson's disease or Alzheimer's disease, there are only a few reports on amyotrophic lateral sclerosis (ALS), a fast progressive and incurable neurodegenerative disease characterized by progressive motor neuron degeneration. Interestingly, initial studies have suggested that ferroptosis might be significantly involved in ALS. Key features of ferroptosis include oxidative stress, glutathione depletion, and alterations in mitochondrial morphology and function, mediated by proteins such as GPX4, xCT, ACSL4 FSP1, Nrf2, and TfR1. Induction of ferroptosis involves small molecule compounds like erastin and RSL3, which disrupt system Xc- and GPX4 activity, respectively, resulting in lipid peroxidation and cellular demise. Mutations in fused in sarcoma (FUS) are associated with familial ALS. Pathophysiological hallmarks of FUS-ALS involve mitochondrial dysfunction and oxidative damage, implicating ferroptosis as a putative cell-death pathway in motor neuron demise. However, a mechanistic understanding of ferroptosis in ALS, particularly FUS-ALS, remains limited. Here, we investigated the vulnerability to ferroptosis in FUS-ALS cell models, revealing mitochondrial disturbances and increased susceptibility to ferroptosis in cells harboring ALS-causing FUS mutations. This was accompanied by an altered expression of ferroptosis-associated proteins, particularly by a reduction in xCT expression, leading to cellular imbalance in the redox system and increased lipid peroxidation. Iron chelation with deferoxamine, as well as inhibition of the mitochondrial calcium uniporter (MCU), significantly alleviated ferroptotic cell death and lipid peroxidation. These findings suggest a link between ferroptosis and FUS-ALS, offering potential new therapeutic targets.