Polystyrene MiPolystyrene Microplastics Induce Radiotherapy Resistance in Lung Cancer by Suppressing Ferroptosis through NF-κB Activationcroplastics Induce Radiotherapy Resistance in Lung Cancer by Suppressing Ferroptosis through NF-κB Activation
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PROVIDER: PRJNA1314704 | ENA |
REPOSITORIES: ENA
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Project description:Aims: Polystyrene microplastics (PS-MPs) are emerging environmental pollutants, but their impact on lung cancer treatment remains unclear. This study investigates how PS-MPs affect radiotherapy efficacy in lung cancer, focusing on their role in ferroptosis regulation and NF-κB pathway activation. Results: PS-MPs were rapidly internalized by lung cancer cells and remained detectable across multiple passages. Exposure to PS-MPs promoted lung cancer cell proliferation, increased mitochondrial length, and elevated Ki67 and c-Myc expression. Following ionizing radiation, PS-MPs significantly attenuated radiation-induced ferroptosis, as evidenced by reduced mitochondrial damage, lipid peroxidation, and GSH depletion. Transcriptomic analysis revealed that PS-MPs activated the NF-κB pathway, leading to increased phosphorylation of IKKβ, IκBα degradation, and enhanced nuclear translocation of NF-κB. In vivo, PS-MPs accumulated in lung tumor-bearing mice, reducing radiotherapy efficacy by increasing tumor volume and weight while decreasing survival rates. Knockdown of NF-κB restored ferroptosis sensitivity and mitigated PS-MPs-induced radioresistance, confirming the NF-κB-dependent inhibition of ferroptosis. Innovation and Conclusion: This study provides the first evidence that PS-MPs impair radiotherapy efficacy in lung cancer by suppressing ferroptosis via NF-κB activation. Unlike previous research focusing on microplastic toxicity in normal tissues, our findings highlight their oncological impact and potential role as an environmental factor influencing cancer therapy resistance. These results emphasize the need for further investigation into microplastics as emerging disruptors of redox homeostasis in oncology and their broader implications for environmental and cancer research.
2025-09-08 | GSE307179 | GEO
Project description:During metastasis, cancer cells face significant survival pressures, including treatment-induced ferroptosis. Adaptation to ferroptosis stress orchestrates the metastasis of colorectal cancer (CRC) cells. However, the reciprocal regulatory mechanisms of ferroptosis and metastasis remain unknown. Here, through a CRISPR–Cas9 screen, we discovered that N-acetylneuraminate synthase (NANS) is a positive regulator of ferroptosis in CRC, regardless of its metabolic function. Moreover, NANS expression is downregulated and is clinically associated with poor prognosis in CRC patients. In a ferroptotic stress environment, NANS is phosphorylated by cyclin-dependent kinase 1 (CDK1) at serine 275 (S275), and phosphorylated NANS (NANS pS275) dissociates from TAK1 and is subsequently ubiquitinated by the E3 ligase ubiquitin-conjugating enzyme E2 N (UBE2N) at lysine 246 (K246) for degradation, which further activates TAK1 and nuclear factor κB (NF-κB) signaling and the expression of the ferroptosis negative regulatory factor FTH1, resulting in ferroptosis resistance and finally promoting metastasis. Furthermore, the NANS pS275 intensity is correlated with the degree of malignancy and the prognosis of CRC patients. Our study revealed that NANS inhibits CRC metastasis by promoting ferroptosis and that the CDK1-mediated phosphorylation of NANS at S275 may guide the utilization of chemical compounds to promote ferroptosis and thus block CRC metastasis.
2025-05-08 | PXD062501 | Pride
Project description:Aims: Oligoasthenozoospermia (OAS) causes male infertility. However, the etiology and pathogenesis of OAS are unclear, and specific therapy is lacking. Ferroptosis contributes to the progress of various diseases; however, its role in OAS is unknown. This study aimed to explore the mechanism of OAS and to find effective treatments. Results: Human OAS sperm exhibits biochemical and morphological hallmarks of ferroptosis. Ferroptosis represents a crucial role in OAS induced by cyclophosphamide (CP) of mice in vivo, and inhibiting ferroptosis can effectively improve OAS. Further search for safe, stable and clinically applicable of natural compounds found Salidroside （Sal）improved the sperm quality of OAS by attenuates ferroptosis-mediated lipid peroxidation in germ cells by increasing the expression of GPX4, and thus ameliorates OAS in vivo. To further investigate at which stage of spermatogenesis Sal acts, the result revealed that Sal increases the expression of GPX4 starting from primary spermatocytes gradually by immunohistochemistry. In vitro, we verified the above results in vivo using a mouse spermatocytes cell line, GC-2 cells. Mechanistically, integrated RNA-Seq and bioinformatic analysis showed that Sal likely promotes GPX4 expression by inhibiting NF-κB Pathway, thereby inhibiting ferroptosis. Innovation: Our findings support the view that ferroptosis plays an important role in patients with OAS, and provide convincing evidence that Sal ameliorates OAS by inhibiting ferroptosis-mediated lipid peroxidation via NF-κB pathway suppression. Conclusions: Thus, ferroptosis plays an important role in OAS, and Sal could ameliorate OAS by attenuating ferroptosis-mediated lipid peroxidation via NF-κB pathway inhibition.
2024-12-01 | GSE249162 | GEO
Project description:Evidence supports the contribution of long non-coding RNAs (lncRNAs) and ferroptosis to traumatic brain injury (TBI) pathogenesis. However, lncRNA regulation in TBI-induced ferroptosis remains poorly understood. Herein, we identified an lncRNA, named noncoding transcript of chemokine (C-C motif) ligand 4 (Ccl4) overlapping (Ntoco), which was upregulated in TBI mice. The upregulation was initiated by hypoxia ischemia induced lower enrichment of H3K27me3 on the Ntoco promoter. Ntoco knockdown inhibited neuron ferroptosis, ameliorated spatial memory and lesion volume following TBI. Ntoco overexpression promoted neuron ferroptosis and recruited microglia to provoke an inflammatory response via Ccl4. Mechanistically, Ntoco facilitated K48-linked ubiquitination and protein degradation by binding to Hnrnpab, which suppressed NF-κB/Lcn2 signal axis activation, including decreased phosphorylation of IkBα, increased phosphorylation of IKKα/β, nuclear translocation of the NF-κB p65 subunit, and elevated Lcn2 expression. These data indicated that targeting Ntoco to mitigate ferroptosis might be a potential therapeutic strategy for TBI.
2024-06-21 | GSE235523 | GEO
Project description:Role of RelB in Suppressing NF-κB Pro-Inflammatory Gene Expression
| PRJNA991535 | ENA
Project description:Immune checkpoint blockade is a powerful oncologic treatment modality for a wide variety of human malignancies. Randomized clinical trials are assessing how best to interdigitate this treatment modality with traditional therapies including radiotherapy. A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities including radiotherapy. Here, we demonstrate that radiotherapy induces tumor cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor cell ferroptosis. Mechanistically, IFN derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically repress SLC7A11, a unit of the glutamate-cystine antiporter xc-, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy.
2020-09-23 | GSE137946 | GEO
Project description:Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL
| PRJNA689774 | ENA
Project description:Role of RelB in Suppressing NF-κB Pro-Inflammatory Gene Expression [RNA-seq]
| PRJNA991540 | ENA
Project description:Apoptotic cells modulate the function of macrophages to control and resolve inflammation. Here, we show that neutrophils induce a rapid and sustained suppression of NF-κB signalling in the macrophage through a unique regulatory relationship which is independent of apoptosis. The reduction of macrophage NF-κB activation occurs through a blockade in transforming growth factor β-activated kinase 1 (TAK1) and IKKβ activation. As a consequence, NF-κB (p65) phosphorylation is reduced, its translocation to the nucleus is inhibited and NF-κB-mediated inflammatory cytokine transcription is suppressed. Gene Set Enrichment Analysis reveals that this suppression of NF-κB activation is not restricted to post-translational modifications of the canonical NF-κB pathway, but is also imprinted at the transcriptional level. Thus neutrophils exert a sustained anti-inflammatory phenotypic reprogramming of the macrophage, which is reflected by the sustained reduction in the release of pro- but not anti- inflammatory cytokines from the macrophage. Together, our findings identify a novel apoptosis-independent mechanism by which neutrophils regulate the mediator profile and reprogramming of monocytes/macrophages, representing an important nodal point for inflammatory control.
| S-EPMC5986789 | biostudies-literature
Project description:Multi-agent chemotherapy still represents the first-line standard-of-care treatment for diffuse large B-cell lymphoma (DLBCL), the most common form of lymphoma in adults. However, the clinicopathological and molecular heterogeneity of DLBCLs poses a major challenge in their successful therapy. At least two major subtypes, i.e. germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL, which differ both in their gene expression profile and in their mutation patterns, have been identified. Here we demonstrate a broad inhibitory effect of dimethyl fumarate (DMF) on the outgrowth of both DLBCL subtypes, even though the molecular basis for its efficacy differs between GCB and ABC DLBCL. Due to high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induced lipid peroxidation and thus ferroptotic cell death in GCB DLBCL. In contrast, in ABC DLBCL inhibition of NF-κB and STAT3 activity essentially contributed to DMF-dependent cytotoxicity. Interestingly, the BCL-2 specific BH3 mimetic ABT-199 or an inhibitor of the ferroptosis suppressor protein 1 synergized with DMF treatment in inducing cell death in DLBCL cell lines. Collectively, our findings identify the established and approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCL.
2021-07-01 | GSE164267 | GEO