Mechanism Of Death Research Articles

Methuosis, Alkaliptosis, and Oxeiptosis and Their Significance in Anticancer Therapy

Understanding morphological, biochemical, and functional aspects of cell death is essential for targeting new cancer therapies. Even though many different mechanisms of cell death are identified, it is crucial to highlight the role of new and lesser-known pathways, including methuosis, alkaliptosis, and oxeiptosis. The aim of this review was to summarize the data about cell death mechanisms—methuosis, alkaliptosis, and oxeiptosis—and their role in cancer treatment. Unique molecular mechanisms and cellular outcomes characterize each of these forms of cell death. This research on methuosis, alkaliptosis, and oxeiptosis provides a better understating of cell death biology and creates novel opportunities for neoplasm management.

GPx1 deficiency confers increased susceptibility to ferroptosis in macrophages from individuals with active Crohn’s disease

Intestinal cell death is a defining feature of Crohn’s disease (CD), a major form of inflammatory bowel disease. The focus on this aspect of enteric inflammation has mainly been on epithelial cells, while other cell types such as stromal and myeloid cells have received less attention. Hypothesising that decreased macrophage viability in an oxidative environment could be a contributing factor to the pathophysiology of CD, we found that monocyte-derived macrophages from individuals with active CD (but not those in clinical disease remission) have increased sensitivity to cell death induced by H2O2. Molecular biology and pharmacological studies ruled out apoptosis and necroptosis, while increased lipid peroxidation and surface expression of the transferrin receptor implicated ferroptosis as the mechanism of the H2O2-induced cell death: this was supported by suppression of H2O2-cytotoxicity by liproxstatin-1, a pharmacological inhibitor of ferroptosis. Selenoproteins are important antioxidants, and selenium deficiency can be a feature of CD. Despite normal dietary intake of selenium, monocyte-derived macrophages and intestinal macrophages in individuals with CD had decreased protein and/or mRNA expression of the selenoprotein, glutathione peroxidase (GPx)-1. Knockdown of GPx1 in macrophages from healthy volunteers resulted in increased H2O2-induced cell death reminiscent of that observed with macrophages from CD. In summary, monocyte-derived macrophages from individuals with CD have increased susceptibility to H2O2-induced ferroptosis cell death, that may be facilitated, at least in part, by reduced expression of the antioxidant GPx1. We suggest that reduced GPx1 in monocytes recruited to the gut and intestinal macrophages renders these cells vulnerable to reactive oxygen species-evoked ferroptosis cell death and that unraveling the participation of this pathway in Crohn’s disease may reveal novel therapeutic approaches to this chronic condition.

High Carbonyl Graphene Oxide Suppresses Colorectal Cancer Cell Proliferation and Migration by Inducing Ferroptosis via the System Xc−/GSH/GPX4 Axis

Background/Objectives: Colorectal cancer (CRC) is characterized by a high rate of both incidence and mortality, and its treatment outcomes are often affected by recurrence and drug resistance. Ferroptosis, an iron-dependent programmed cell death mechanism triggered by lipid peroxidation, has recently gained attention as a potential therapeutic target. Graphene oxide (GO), known for its oxygen-containing functional groups, biocompatibility, and potential for functionalization, holds promise in cancer treatment. However, its role in ferroptosis induction in CRC remains underexplored. The objective of this study was to investigate the effects of High Carbonyl Graphene Oxide (HC-GO) on ferroptosis in CRC and elucidate the underlying mechanisms. Methods: In vitro assays were conducted to evaluate the impact of HC-GO on CRC cell proliferation, mitochondrial function, iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) production. The ferroptosis inhibitor Fer-1 was used to confirm the role of ferroptosis in HC-GO’s anti-tumor effects. In vivo, the anti-tumor activity of HC-GO was assessed in a CRC xenograft model, with organ toxicity evaluated. Results: HC-GO significantly inhibited CRC cell proliferation, induced mitochondrial damage, and enhanced iron accumulation, lipid peroxidation, and ROS production. It also downregulated the ferroptosis-inhibiting proteins GPX4 and SLC7A11, which were reversed by Fer-1, confirming the involvement of ferroptosis in HC-GO’s anti-cancer effects. In vivo, HC-GO significantly suppressed tumor growth without noticeable toxicity to vital organs. Conclusions: HC-GO triggered ferroptosis in CRC cells by suppressing the System Xc−/GSH/GPX4 pathway, providing a novel therapeutic strategy for CRC treatment. These findings suggest HC-GO as a promising nanomedicine for clinical application, warranting further investigation to explore its potential in CRC therapy.

Frailty and fear of death among geriatric patients in critical care units: A mixed methods study.

Frailty, a geriatric syndrome characterized by decreased resilience, is a known risk factor for mortality in critical care settings and can significantly impact a patient's perception of their own health and prognosis. To explore the relationship between frailty and fear of death in geriatric patients admitted to critical care units. A convergent parallel mixed methods design was applied. Data were collected from 247 geriatric patients in critical care units from March 2023 to February 2024. Quantitative data included clinical frailty score and death anxiety questionnaire. Qualitative data were gathered through semi-structured interviews with a subset of 34 participants. Quantitative analysis involved descriptive statistics, correlation analysis and multiple linear regression. Qualitative data were analysed thematically using Braun and Clarke's approach. Quantitative analysis revealed a positive significant correlation between frailty and death anxiety (r = 0.19, p = 0.003). Additionally, regression analysis identified age (B = 0.69, 95% CI [0.22, 1.15], p = 0.004), lack of social support (B = 2.88, 95% CI [0.28, 5.47], p = 0.030), lower income (B = -5.33, 95% CI [-9.03, -1.63], p = 0.005) and higher frailty scores (B = 0.83, 95% CI [0.10, 1.56], p = 0.025) as significant predictors of increased death anxiety. Qualitative findings yielded four key themes: the impact of frailty on perception of mortality, the psychological and emotional dimensions of fear of death, the role of the critical care unit environment on fear of death and coping mechanisms and support. Frailty in geriatric critically ill patients heightened death anxiety due to physical decline, existential worries and the overwhelming critical care environment. This study can help nurses provide more personalized care to geriatric patients by addressing both their physical frailty and psychological needs related to fear of death. This, in turn, can improve the quality of care and enhance patient satisfaction.

Metal-Dependent Cell Death in Renal Fibrosis: Now and in the Future

Renal fibrosis is a common final pathway underlying nearly almost all progressive kidney diseases. Metal ions are essential trace elements in organisms and are involved in important physiological activities. However, aberrations in intracellular metal ion metabolism may disrupt homeostasis, causing cell death and increasing susceptibility to various diseases. Accumulating evidence suggests a complex association between metal-dependent cell death and renal fibrosis. In this article, we provide a comprehensive overview of the specific molecular mechanisms of metal-dependent cell death and their crosstalk, up-to-date evidence supporting their role in renal fibrosis, therapeutic targeting strategies, and research needs, aiming to offer a rationale for future clinical treatment of renal fibrosis.

Radionuclide treatments of cancer: molecular mechanisms, biological responses, histopathological changes, and role of PET imaging.

Radiation treatments [radiotherapy and radionuclide treatments (RNTs)] are one of the main and effective treatment modalities of cancer. Globally, the number of cancer patients treated with radionuclides are much less as compared to number of radiotherapy cases but with the development of new radiotracers, most notably 177Lu and 225Ac-labeled prostate-specific membrane antigen ligands, and 223Ra-dichloride for prostate cancer and 177Lu-somatostatin analogs for neuroendocrine tumors, there is a significant rise in RNTs in the last decade. As therapeutic applications of nuclear medicine is on the rise, the aim of this review is to summarize biological responses to radiation treatments and molecular mechanisms of radiation-induced cell death (e.g. ionization, DNA damages such as double-strand breaks, DNA repair mechanisms, types of cell deaths such as apoptosis, necrosis, and immunogenic cell death), histopathological changes with radiation treatments, and role of PET imaging in RNTs as part of radionuclide theranostics for selecting and planning patients for RNTs, dosimetry, predicting and assessing response to RNTs, predicting toxicities, and other possible PET findings which may be seen after RNTs such as activation of immune system.

Decoding ferroptosis: transforming orthopedic disease management

As a mechanism of cell death, ferroptosis has gained popularity since 2012. The process is distinguished by iron toxicity and phospholipid accumulation, in contrast to autophagy, apoptosis, and other cell death mechanisms. It is implicated in the advancement of multiple diseases across the body. Researchers currently know that osteosarcoma, osteoporosis, and other orthopedic disorders are caused by NRF2, GPX4, and other ferroptosis star proteins. The effective relief of osteoarthritis symptoms from deterioration has been confirmed by clinical treatment with multiple ferroptosis inhibitors. At the same time, it should be reminded that the mechanisms involved in ferroptosis that regulate orthopedic diseases are not currently understood. In this manuscript, we present the discovery process of ferroptosis, the mechanisms involved in ferroptosis, and the role of ferroptosis in a variety of orthopedic diseases. We expect that this manuscript can provide a new perspective on clinical diagnosis and treatment of related diseases.

Alterations in the proteomes of HepG2 and IHKE cells inflicted by six selected mycotoxins.

Toxic fungal secondary metabolites, referred to as mycotoxins, emerge in moldy food and feed and constitute a potent but often underestimated health threat for humans and animals. They are structurally diverse and can cause diseases after dietary intake even in low concentrations. To elucidate cellular responses and identify cellular targets of mycotoxins, a bottom-up proteomics approach was used. We investigated the effects of the mycotoxins aflatoxin B1, ochratoxin A, citrinin, deoxynivalenol, nivalenol and penitrem A on the human hepatoblastoma cell line HepG2 and of ochratoxin A and citrinin on the human kidney epithelial cell line IHKE. Incubations were carried out at sub-cytotoxic concentrations to monitor molecular effects before acute cell death mechanisms predominate. Through these experiments, we were able to detect specific cellular responses that point towards the mycotoxins' mode of action. Besides very well-described mechanisms like the ribotoxicity of the trichothecenes, we observed not yet described effects on different cellular mechanisms. For instance, trichothecenes lowered the apolipoprotein abundance and aflatoxin B1 affected proteins related to inflammation, ribogenesis and mitosis. Ochratoxin A and citrinin upregulated the minichromosomal maintenance complex and nucleotide synthesis in HepG2 and downregulated histones in IHKE. Penitrem A reduced enzyme levels of the sterol biosynthesis. These results will aid in the elucidation of the toxicodynamic properties of this highly relevant class of toxins.

Mechanisms of H2pmen-Induced cell death: Necroptosis and apoptosis in MDA cells, necrosis in MCF7 cells

Mechanisms of H2pmen-Induced cell death: Necroptosis and apoptosis in MDA cells, necrosis in MCF7 cells

Ferroptosis driven by nanoparticles for tackling glioblastoma

Ferroptosis driven by nanoparticles for tackling glioblastoma

Cervical Cancer Cells Use the CD95 and IL-2 Pathways to Promote Their Proliferation and Survival

Cervical cancer is a global health problem; therapies focused on eliminating tumour cells and strengthening different immunotherapies are in development. However, it has been observed that cervical tumour cells can evade cell death mechanisms and generate immune system molecules to promote their proliferation and metastasis. In this context, we analysed the role of the IL-2 and CD95 pathways, essential molecules in activating the immune system and eliminating tumour cells. However, it is important to analyse their role in cervical tumour cells because these cells could be using these pathways to proliferate. In this study, we found that SiHa and HeLa cells respond to treatment, with 10 IU/mL of IL-2 inducing their proliferation and 100 IU/mL of IL-2 decreasing their proliferation. We also observed that they express a high percentage of the CD95 receptor and its ligand (CD95L) and that treatment with CD95 agonist antibodies at low doses increases cell proliferation. Furthermore, simultaneous treatment with high doses of IL-2 plus CD95 agonist antibody positively regulates LC3B accumulation. We did not observe apoptosis under any of the treatments carried out. In conclusion, cervical tumour cells can use the IL-2 and CD95 pathways to induce their proliferation and potentially activate cytoprotective mechanisms for survival.

Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells

Gambogic acid (GA) is a naturally active compound extracted from the Garcinia hanburyi with various anticancer activities. However, whether GA induces pyroptosis (a newly discovered inflammation-mediated programmed cell death mechanism) in ovarian cancer (OC) has not yet been reported. This study revealed that GA treatment reduced cell viability by inducing pyroptosis in OC cell lines. Typical pyroptosis morphological manifestations such as cell swelling with large bubbles and loss of cell membrane integrity, were observed. Cleaved caspase-3 and GSDME-N levels increased after GA treatment, and knocking out GSDME or using a caspase-3 inhibitor could switch GA-induced cell death from pyroptosis to apoptosis, indicating GA induced caspase-3/GSDME-dependent pyroptosis. Furthermore, this research indicated that GA significantly increased reactive oxygen species (ROS) and p53 phosphorylation. OC cells pretreated with ROS inhibitor N-Acetylcysteine (NAC) and the specific p53 inhibitor pifithrin-μ could completely reverse the pyroptosis post-treatment. Elevated p53 and phosphorylated p53 reduced mitochondrial membrane potential (MMP) and Bcl-2, increase the expression of Bax, and damage mitochondria by releasing cytochrome c to activate the downstream pyroptosis pathway. Different doses of GA inhibited tumor growth in ID8 tumor-bearing mice, and high-dose GA increased in tumor-infiltrating lymphocytes CD3, CD4, and CD8 were detected in tumor tissues. Notably, the expressions of GSDME-N, cleaved caspase-3 and other proteins were increased in tumor tissues with high-dose GA groups. These findings demonstrate that GA-treated OC cells could induce GSDME-mediated pyroptosis through the ROS/p53/mitochondria signaling pathway and caspase-3/-9 activation. Thus, GA is a promising therapeutic agent for OC treatment

Novel cuprotosis-related gene signature: a prognostic indicator and regulator of the glioma immune microenvironment.

Glioma is a primary malignant brain tumor with a poor prognosis. Glioma-related biomarkers need to be identified to enable the personalized treatment of and predict the prognosis of glioma patients. Cuproptosis is an unusual mechanism of cell death, and is closely associated with disease progression and the immune-microenvironment of the tumor. However, the function of cuproptosis in glioma is still unclear, therefore the aim of this study was to investigate the role of cuproptosis-related genes in gliomas. We examined the relationship between cuproptosis and glioma using the clinical and expression data of glioma tumors from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). First, we determined the rate of somatic mutations and copy number variations (CNVs) of 51 copper homeostasis-related genes and studied their correlation with prognosis. We then identified three molecular subgroups of copper homeostasis-related genes linked to prognosis. We discovered that different subgroups had distinct immune and biological features. We then developed a prognostic model by least absolute shrinkage and selection operator (LASSO) regression that comprised four cuproptosis-related genes; that is, a solute carrier family 31 member A1 (SLC31A1), microtubule-associated protein tau (MAPT), ATPase beta (ATP7B), and six-transmembrane epithelial antigen of prostate 3 (STEAP3). This model was found to have strong prognostic ability in the CGGA cohort (P<0.05). We investigated the function of copper homeostasis-related genes in neuroglioma and their relationship with tumor immunology. Our in-depth analyses revealed that these biomarkers are useful for diagnostic and prognostic purposes and could be used to guide our understanding of the progression of and treatment of glioma tumorigenesis.

NIR-II Photoacoustic Imaging-Guided Chemo-Photothermal Therapy Using PA1094T Combined with Anti-CD47 Antibody: Activating Pyroptosis against Orthotopic Glioblastoma.

Treating glioblastoma (GBM) with single-agent chemotherapy is often ineffective due to inefficient drug delivery and the immunosuppressive tumor microenvironment, which leads to drug resistance. Strategies that activate programmed cell death mechanisms and repolarized tumor-associated macrophages toward an antitumoral M1-like phenotype can help reverse the immunosuppressive tumor microenvironment. In this study, a novel approach using NIR-II (1000-1700nm) photoacoustic imaging (PAI)-guided chemo-photothermal therapy is presented. NIR-II imaging, with its superior tissue penetration and reduced background noise, enables precise tumor targeting. A targeted nano prodrug is developed using poly (lactic-co-glycolic acid) nanoparticles loaded with A1094 dye and temozolomide (TMZ), coupled with an anti-CD47 antibody. This system employs synergistic chemo-photothermal therapy activated by NIR-II light, inducing apoptosis, pyroptosis, and T-cell activation. PAI provides rapid, point-of-care GBM diagnosis, and highlighted the effective targeting of the PA1094T nanoplatform. In a recurrent GBM model, the combination of PA1094T and anti-CD47 antibody significantly enhances cancer cell phagocytosis and effectively remodels the immunosuppressive microenvironment, resulting in better therapeutic outcomes compared to conventional therapies. These results indicate that this NIR-II PAI-guided drug cocktail therapy is a promising strategy for treating GBM, potentially addressing drug resistance and improving treatment efficacy through enhanced targeting and immunomodulation.

Improving medical certification of cause of death in Assiut University Children Hospital: an intervention study

IntroductionDeath certification is a health indicator and a public health surveillance tool. High-quality death certificate ensures reliability of mortality statistics used to direct the arranging of health-related programs and leading assessments of research and proper healthcare outcomes. The World Health Organization (WHO) puts Egypt in the group of ‘low quality’ death registration data. The aim of this study was to evaluate the impact of composite training and audit intervention on accurate completion of death notification forms (DNFs) in Assiut University Children Hospital (AUCH) that has an average monthly mortality of 120 children’s deaths.MethodsA Quasi-experimental study design was conducted among residents of AUCH. The intervention consisted of 1- Preparing training material with basic information on how to report causes of death according to WHO criteria and case scenarios extracted from the medical records of children who died at AUCH, 2- One hundred residents of the AUCH were trained in one day workshops in 4 groups, with a pre-post knowledge assessment questionnaire. 3- A weekly audit of a sample of 10–15 DNFs was done for six months with reporting of findings to quality assurance director of the hospital.ResultsEighty- nine physicians completed the pre-post knowledge assessment with significant increase in knowledge score after the intervention (15.7 ± 3.2 vs. 11.9 ± 2.8). There was a significant decrease in the errors of reporting on the DNFs. The main improvement was in decrease from 90 to 18% in reporting the mechanism of death, and significant decline in writing cause of death in Arabic language only.ConclusionAccurate reporting of the medical cause of death can be achieved by educational intervention targeting physicians with institutionalizing of audit system for continuous quality improvement.

Cupric Doping Hollow Prussian Blue Nanoplatform for Enhanced Cholesterol Depletion: a Promising Strategy for Breast Cancer Therapy and Metastasis Inhibition.

The dysregulated cholesterol metabolism in breast cancer cells drives malignancy, invasion, and metastasis, emphasizing the significance of reducing abnormal cholesterol accumulation for effective cancer treatment and metastasis inhibition. Despite its promise, cholesterol oxidase (ChOx) encounters challenge due to limited catalytic efficiency and susceptibility to harsh conditions. To overcome these hurdles, biocompatible nanoplatforms (Cu-HPB/C) tailored for efficient cholesterol depletion are introduced. Cu2+-doped hollow Prussian blue (Cu-HPB) acts as a carrier, shelter, and enhancer for ChOx, bolstering tumor-targeting ability, stability, and enzymatic activity. Tumor-responsive released Cu2+ notably augments ChOx activity, facilitating cholesterol depletion and disrupting lipid rafts, thereby impeding cell invasion and migration. Additionally, H2O2 generated from the oxidase reaction enhances Cu-HPB's chemo dynamic therapeutic efficacy. Transcriptomic analysis validates Cu-HPB/C's impact on cholesterol homeostasis and reveals cell death mechanisms including oxidative stress, ferroptosis, cuproptosis, and apoptosis. Demonstrating therapeutic efficacy in both 4T1 tumor subcutaneous and metastasis mouse models, the study presents a direct and effective strategy for tumor therapy and metastasis inhibition through enhanced cholesterol depletion.

The protumorigenic enzyme GPAT2 inhibits arachidonic acid-triggered apoptosis in breast cancer

BackgroundCancer is a significant health challenge and the leading cause of mortality globally. Tumor cells use multiple mechanisms to acquire their distinctive capacity for uncontrolled proliferation, one of which is the evasion of apoptosis. It has been shown that in breast, colon, and liver cancer, evasion of apoptosis is associated with the overexpression of enzymes that metabolize arachidonic acid (AA) because free AA is a strong inducer of apoptosis. Glycerol−3-phosphate acyltransferase 2 (GPAT2) is a key enzyme in AA metabolism and is highly expressed in breast and colon cancer, where it promotes the development of essential tumor features.MethodsIn this work, a model of GPAT2 silencing in the human breast cancer-derived cell line MDA-MB-231 was used, and the cells were exposed to exogenous AA. The role of GPAT2 in AA-induced cell death was studied using MTT and TUNEL assays and measurements of caspase activity. The underlying molecular mechanism of cell death was assessed by qRT‒PCR.ResultsThe results showed that AA reduced cell viability only in GPAT2-silenced cells, and that this cell death was a consequence of an apoptotic process involving BNIP3 overexpression. Additionally, it was demonstrated that GPAT2 silencing triggered a compensatory mechanism by overexpressing other genes involved in AA utilization for eicosanoid biosynthesis.ConclusionsWe concluded that GPAT2 expression is necessary to prevent AA-induced apoptotic cell death in MDA-MB-231 cells and that the overexpression of other AA-metabolizing genes is not sufficient to compensate for the lack of GPAT2 and prevent apoptosis.

Mitochondrial dysfunction in Parkinson's disease.

The exact cause of nigral cell death in Parkinson's disease (PD) is still unknown. However, research on MPTP-induced experimental parkinsonism has significantly advanced our understanding. In this model, it is widely accepted that mitochondrial respiratory failure is the primary mechanism of cell death. Studies have shown that a toxic metabolite of MPTP inhibits Complex I and alpha-ketoglutarate dehydrogenase activities in mitochondria. Since then, many research groups have focused on mitochondrial dysfunction in PD, identifying deficiencies in Complex I or III in PD patients' brains, skeletal muscle, and platelets. There is some debate about the decline in mitochondrial function in peripheral organs. However, since α-synuclein, the main component protein of Lewy bodies, accumulates in peripheral organs, it is reasonable to consider PD a systemic disease. Additionally, mutant mitochondrial DNA with a 4,977 base pair deletion has been found in the brains of PD patients, suggesting that age-related accumulation of deleted mtDNA is accelerated in the striatum and may contribute to the pathophysiology of PD. While the cause of PD remains unknown, mitochondrial dysfunction is undoubtedly a factor in cell death in PD. In addition, the causative gene for familial PD, parkin (now PRKN), and PTEN-induced putative kinase 1 (PINK1), both gene products are also involved in mitochondrial quality control. Moreover, we have successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system. There is no doubt that mitochondrial dysfunction contributes to cell death in PD.

Research progress of mechanism of acupuncture and moxibustion on prevention and treatment of Alzheimer's disease based on the neuronal cell cycle re-entry

Alzheimer's disease (AD) is the most common type of dementia. Studies have shown that neuronal cell cycle re-entry is an abnormal change in the early stage of AD, and it is also one of the key reasons for mediating neuronal death. The mechanism of acupuncture and moxibustion in treating AD may be related to the regulation of abnormal cell cycle. In this article, we reviewed the occurrence of AD neuronal cell cycle re-entry and its mediated cell death mechanism, listed the factors affecting neuronal cell cycle re-entry, explored the possible mechanism of acupuncture and moxibustion in preventing and treating AD by regulating AD cell cycle protein, AD neuronal cell cycle re-entry influencing factors (β-amyloid protein and Tau protein phosphorylation level, oxidative stress, brain-derived neurotrophic factor), the multi-target regulation of neuronal cell cycle re-entry, so as to provide reference for the application and research of acupuncture and moxibustion in preventing and treating AD.

Dimethyl fumarate and extracorporeal photopheresis combination-therapy synergize in inducing specific cell death and long-term remission in cutaneous T cell lymphoma.

Primary cutaneous T cell lymphomas (CTCL) are characterized by high relapse rates to initially highly effective therapies. Combination therapies have proven beneficial, particularly if they incorporate extracorporeal photopheresis (ECP). The NF-κB inhibitor dimethyl fumarate (DMF) has proven a new, effective drug in CTCL in a clinical phase II study. In vitro experiments with patient-derived SS cells and the CTCL cell lines HH, HuT 78, and SeAx revealed a synergistic effect of DMF and ECP on cell death induction in CTCL cells. Furthermore, an additional increase in the capacity to inhibit NF-κB in CTCL was detected for the combination treatment compared to DMF monotherapy. The same synergistic effects could be measured for ROS production via decreased Thioredoxin reductase activity and glutathione levels. Consequently, a cell death inhibitor screen indicated that the DMF/ECP combination treatment induces a variety of cell death mechanisms in CTCL. As a first step into clinical translation, 4 patients were already treated with the DMF/ECP combination therapy with an overall response rate of 100% and a time to next treatment in skin and blood of up to 57 months. Therefore, our study introduces the combination treatment of DMF and ECP as a highly effective and long-lasting CTCL therapy.