Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1207287 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31910539_1.fastq.gz | Fastqsanger.gz | |||
| SRR31910539_2.fastq.gz | Fastqsanger.gz | |||
| SRR31910540_1.fastq.gz | Fastqsanger.gz | |||
| SRR31910540_2.fastq.gz | Fastqsanger.gz | |||
| SRR31910541_1.fastq.gz | Fastqsanger.gz |
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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:Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. Understanding the dysregulated epigenetics governing LUAD progression is pivotal for identifying therapeutic targets. CBX4, a chromobox protein, is reported to be upregulated in LUAD. However, its regulatory role in LUAD progression warrants in-depth investigation. This study highlights the dual impact of CBX4 on LUAD proliferation and metastasis. Through a series of rigorous in vitro and in vivo experiments, we elucidate that CBX4 functions in promoting LUAD proliferation via upregulating PHGDH expression while concurrently suppressing LUAD metastasis by inhibiting ZEB2 transcription. Further investigation into the underlying mechanism reveals CBX4’s intricate interactions with distinct epigenetic factors. The inhibition of ZEB2 transcription involves CBX4-mediated recruitment of canonical PRC1 (cPRC1), establishing H2K119ub on the ZEB2 promoter. Simultaneously, CBX4 facilitates PHGDH transcription through interaction with GCN5, inducing heightened histone acetylation on the PHGDH promoter. These findings underscore CBX4's pivotal role as a regulator of LUAD progression, emphasizing its diverse transcriptional regulatory functions contingent upon interactions with specific epigenetic partners. Understanding the nuanced interplay between CBX4 and epigenetic factors sheds light on potential therapeutic avenues in LUAD.
2024-01-05 | GSE252230 | GEO
Project description:Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. Understanding the dysregulated epigenetics governing LUAD progression is pivotal for identifying therapeutic targets. CBX4, a chromobox protein, is reported to be upregulated in LUAD. However, its regulatory role in LUAD progression warrants in-depth investigation. This study highlights the dual impact of CBX4 on LUAD proliferation and metastasis. Through a series of rigorous in vitro and in vivo experiments, we elucidate that CBX4 functions in promoting LUAD proliferation via upregulating PHGDH expression while concurrently suppressing LUAD metastasis by inhibiting ZEB2 transcription. Further investigation into the underlying mechanism reveals CBX4’s intricate interactions with distinct epigenetic factors. The inhibition of ZEB2 transcription involves CBX4-mediated recruitment of canonical PRC1 (cPRC1), establishing H2K119ub on the ZEB2 promoter. Simultaneously, CBX4 facilitates PHGDH transcription through interaction with GCN5, inducing heightened histone acetylation on the PHGDH promoter. These findings underscore CBX4's pivotal role as a regulator of LUAD progression, emphasizing its diverse transcriptional regulatory functions contingent upon interactions with specific epigenetic partners. Understanding the nuanced interplay between CBX4 and epigenetic factors sheds light on potential therapeutic avenues in LUAD.
2024-01-05 | GSE252181 | GEO
Project description:Smooth muscle cell (SMC) loss is the characteristic feature in the pathogenesis of aortic dissection (AD), and ferroptosis is a novel iron-dependent regulated cell death driven by the excessive lipid peroxidation accumula_x0002_tion. However, whether targeting ferroptosis is an effective approach for SMC loss and AD treatment remains unclear. Here, we found that the iron level, ferroptosis-related molecules TFR, HOMX1, ferritin and the lipid peroxidation product 4-hydroxynonenal were increased in the aorta of AD. Then, we screened several inhibitors of histone methyltransferases and found that BRD4770 had a protective effect on cystine deprivation-, imidazole ketone erastin- or RSL3-induced ferroptosis of SMCs. The classic ferroptosis pathways, System Xc--GPX4, FSP1- CoQ10 and GCH1-BH4 pathways which were inhibited by ferroptosis inducers, were re-activated by BRD4770 via inhibiting mono-, di- and tri- methylated histone H3 at lysine 9 (H3K9me1/2/3). RNA-sequencing analysis revealed that there was a positive feedback regulation between ferroptosis and inflammatory response, and BRD4770 can reverse the effects of inflammation activation on ferroptosis. More importantly, treatment with BRD4770 attenuated aortic dilation and decreased morbidity and mortality in a β-Aminopropionitrile monofumarate-induced mouse AD model via inhibiting the inflammatory response, lipid peroxidation and fer_x0002_roptosis. Taken together, our findings demonstrate that ferroptosis is a novel and critical pathological mechanism that is involved in SMC loss and AD development. BRD4770 is a novel ferroptosis inhibitor and has equivalent protective effect to Ferrostatin-1 at the optimal concentration. Translating insights into the anti-ferroptosis ef_x0002_fects of BRD4770 may reveal a potential therapeutic approach for targeting SMC ferroptosis in AD.
2024-07-16 | GSE272018 | GEO
Project description:InactivatingSTK11/KEAP1 co-mutations are genomic drivers of primary resistance totherapies and worse outcome in KRAS-mutatedlung adenocarcinoma(LUAD), however the underlying mechanisms is still not understood.Here we provide a transcriptomic analysis of over 3800 “real-world” LUAD cases that concomitant loss of STK11 and KEAP1 in a KRAS-mutant tumorleads to significant upregulation of fatty acid metabolism, and redox signaling pathways with significantly high expression of ferroptosis evasion genes, SCD1 and SLC7A11. Global transcriptomics and kinase arrays demonstrate the role SCD1 in regulating AKT/GSK3β/NRF2 signaling mediated modulation of SLC7A11 and GSH metabolism. Furthermore, in a lipidomic assay, SCD1 knockout led to regulation of SFA-MUFA levels that promoted ferroptosis. SCD1 inhibition reverses the resistance to ferroptosis induction promoted by STK11/KEAP1 loss inmouse models. These data provide evidence that SCD1 protects ferroptosis induction and therapeutic targeting of this pathway is a promising translational strategy in KRAS mutant LUADs with concomitant loss ofSTK11 and KEAP1.
2025-02-07 | GSE262660 | GEO
Project description:Spliceosomal GTPase EFTUD2 (Elongation factor Tu GTP binding domain containing 2) is a causative gene for mandibulofacial dysostosis with microcephaly (MFDM) in humans, a complex syndrome with multiple neurological symptoms including cerebellar hypoplasia and motor dysfunction. How EFTUD2 deficiency contributes to these neurological symptoms remains elusive. In this study, we demonstrate that specific ablation of Eftud2 in cerebellar Purkinje cells (PCs) in mice results in severe ferroptosis, PC degeneration, dyskinesia and cerebellar atrophy, which are similar to phenotypes observed in MFDM patients. Mechanistically, Eftud2 promotes the expression of Scd1 and Gch1, upregulates monounsaturated fatty acids-phospholipids (MUFA-PLs), and enhances systematic antioxidant activity, thereby suppressing ferroptotic cell death of PCs. Importantly, inhibiting ferroptosis efficiently rescues PC loss and motor deficits in Eftud2 cKO mice. Our data reveals a novel role of Eftud2 in maintaining the survival of PCs, and that inhibiting ferroptosis via pharmacological or genetic means may be a promising therapeutic strategy for EFTUD2 deficiency-induced MFDM and related disorders.
2024-12-31 | GSE252271 | GEO
Project description:The activation of pulmonary endothelial cells (ECs) triggers the occurrence of lung injury and is a hallmark of sepsis-associated acute respiratory distress syndrome(ARDS). Aberrant metabolism favoring glycolysis plays a pivotal role in the pathogenesis of sepsis-induced EC activation. Herein we demonstrate that glycolysis-related histone lactylation, represented by H3K14 lactylation (H3K14la), drives sepsis-associated EC activation and lung injury. Accordingly, H3K14la level is elevated in injured lung tissue and activated ECs. Inhibition of lactate production suppresses both H3K14la levels and EC activation in response to lipopolysaccharide (LPS). We also show that lactate-dependent H3K14la is enriched at the promoters of ferroptosis-related genes, thereby inducing ferroptosis in ECs, and inhibiting ferroptosis effectively ameliorates EC activation. Taken together, elevated lactate in sepsis modulates EC activation and lung injury via histone lactylation and manipulation of glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for the treatment of sepsis-associated ARDS.
2023-01-01 | GSE212087 | GEO
Project description:Lung adenocarcinoma (LUAD) remains the leading cause of cancer deaths worldwide. Apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme integral to DNA repair and redox signaling, is notably upregulated in various cancers, including LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, correlates with poor prognosis in LUAD patients strongly. Using human LUAD cell models and a KRAS-driven genetically engineered mouse model (GEMM), we show that APE1 deletion hampers cell proliferation and tumor growth, highlighting its role in tumorigenesis. Mechanistically, APE1 promoted the transcription of urea cycle genes CPS1 and ARG2 by modulating the presence of G-quadruplex (G4) structures in their promoter regions. Loss of APE1 disrupts the urea cycle and pyrimidine metabolism, inducing metabolic reprogramming and growth arrest, which can be rescued by CPS1 or pyrimidine restoration. These findings uncover APE1’s role in metabolic regulation via G4-mediated transcription, providing a potential therapeutic target LUAD patients with elevated APE1 expression.
2024-12-06 | GSE271726 | GEO
Project description:Gamma interferon (IFN-γ) was reported to exhibit anti-tumor effects via inducing ferroptosis. Based on genome-wide CRISPR/Cas9 knockout screens, we discovered that cAMP response ele-ment binding protein (CREB) regulated transcription coactivator3 (CRTC3) protects tumor cells from drug induced ferroptosiis and is a significant resister of IFN-γ treatment in hepatocellular car-cinoma (HCC). Mechanically, CRTC3 knockout alters tumor cell lipid pattern and increases the abundance of polyunsaturated fatty acids (PUFAs), which facilitates lipid peroxidation and renders HCC cells susceptible to ferroptosis inducers. To scavenge accumulated lipid peroxides (LPO) and maintain redox equilibrium, HCC cells upregulate SLC7A11 expression to enhance the activity of glutamate-cystine antiporter (system xc-). As IFN-γ inhibiting system xc-, simultaneously treatment of IFN-γ disrupts the compensatory mechanism, and generates a synergistic effect with CRTC3 knockout to facilitate ferroptosis. The sensitizing effect of CRTC3 depletion was further confirmed in typical ferroptosis inducers including RSL3, Erastin and Sorafeinib. Here, we reported a hitherto unexpected role of CRTC3 in regulating PUFAs metabolism and ferroptosis. Targeting the CRTC3 signaling in combination with ferroptosis inducers may represent a viable approach to treat cancer and overcome drug resistance in HCC.
2025-06-24 | GSE206905 | GEO
Project description:Gamma interferon (IFN-γ) was reported to exhibit anti-tumor effects via inducing ferroptosis. Based on genome-wide CRISPR/Cas9 knockout screens, we discovered that cAMP response ele-ment binding protein (CREB) regulated transcription coactivator3 (CRTC3) protects tumor cells from drug induced ferroptosiis and is a significant resister of IFN-γ treatment in hepatocellular car-cinoma (HCC). Mechanically, CRTC3 knockout alters tumor cell lipid pattern and increases the abundance of polyunsaturated fatty acids (PUFAs), which facilitates lipid peroxidation and renders HCC cells susceptible to ferroptosis inducers. To scavenge accumulated lipid peroxides (LPO) and maintain redox equilibrium, HCC cells upregulate SLC7A11 expression to enhance the activity of glutamate-cystine antiporter (system xc-). As IFN-γ inhibiting system xc-, simultaneously treatment of IFN-γ disrupts the compensatory mechanism, and generates a synergistic effect with CRTC3 knockout to facilitate ferroptosis. The sensitizing effect of CRTC3 depletion was further confirmed in typical ferroptosis inducers including RSL3, Erastin and Sorafeinib. Here, we reported a hitherto unexpected role of CRTC3 in regulating PUFAs metabolism and ferroptosis. Targeting the CRTC3 signaling in combination with ferroptosis inducers may represent a viable approach to treat cancer and overcome drug resistance in HCC.
2025-06-24 | GSE206906 | GEO