TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis

Zhou, Ren‐Peng; Chen, Yong; Li, Shufang; Wei, Xin; Hu, Wei; Tang, Simin; Ding, Jie; Fu, Wanjin; Zhang, Hailin; Chen, Fan; Hao, Wen‐Juan; Lin, Yi; Zhu, Rendi; Wang, Ke; Dong, Lei; Zhao, Yingjie; Feng, Xiaowen; Chen, Feihu; Ding, Changhai; Hu, Wei

doi:10.1016/j.redox.2022.102411

Cited by 53 publications

(28 citation statements)

References 49 publications

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“…NADPH oxidase 4 (NOX4) is a member of the NOX family and generates H 2 O 2 by catalyzing the electron transfer from NADPH to O 2 . , Since the activity of NOX4 is substantially regulated by its concentration, Erastin-induced NOX4 upregulation is expected to increase the concentration of H 2 O 2 in the intracellular environment, thereby supporting the reaction with Cu + ions in the nanoreactor. , To monitor the NOX4 expression after incubation with nanoreactors, an immunofluorescence assay was constructed. As shown in Figure E, after uptake, the released Erastin effectively activated NOX4 protein expression in tumor cells under both normoxia and hypoxia conditions.…”

Section: Resultsmentioning

confidence: 99%

Oxygen Self-Generating Nanoreactor Mediated Ferroptosis Activation and Immunotherapy in Triple-Negative Breast Cancer

Yang

et al. 2023

ACS Nano

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The hypoxia microenvironment of solid tumors poses a technological bottleneck for ferroptosis and immunotherapy in clinical oncology. Nanoreactors based on special physiological signals in tumor cells are able to avoid various tumor tolerance mechanisms by alleviating the intracellular hypoxia environment. Herein we reported a nanoreactor Cu 2−x Se that enabled the conversion of Cu elements between Cu + and Cu 2+ for the generation of O 2 and the consumption of intracellular GSH content. Furthermore, to enhance the catalytic and ferroptosis-inducing activities of the nanoreactors, the ferroptosis agonist Erastin was loaded on the ZIF-8 coating on the surface of Cu 2−x Se to up-regulate the expression of NOX4 protein, increase the intracellular H 2 O 2 content, catalyze the Cu + to produce O 2 and activate ferroptosis. In addition, the nanoreactors were simultaneously surface functionalized with PEG polymer and folic acid molecules, which ensured the in vivo blood circulation and tumor-specific uptake. In vitro and in vivo experiments demonstrated that the functionalized self-supplying nanoreactors can amplify the ability to generate O 2 and consume intracellular GSH via the interconversion of Cu elements Cu + and Cu 2+ , and impair the GPX4/GSH pathway and HIF-1α protein expression. At the same time, by alleviating the intracellular hypoxia environment, the expression of miR301, a gene in the secreted exosomes was decreased, which ultimately affected the phenotype polarization of TAMs and increased the content of IFN γ secreted by CD8 + T cells, which further promoted the ferroptosis induced by Erastin-loaded nanoreactors. This combined therapeutic strategy of activating the tumor immune response and ferroptosis via self-supplying nanoreactors provides a potential strategy for clinical application.

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Section: Resultsmentioning

confidence: 99%

Oxygen Self-Generating Nanoreactor Mediated Ferroptosis Activation and Immunotherapy in Triple-Negative Breast Cancer

Yang

et al. 2023

ACS Nano

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“…A study by Luo and Zhang (2021) shows that the lipopolysaccharide (LPS) stimulation reduces GPX4, SLC7A11, SLC3A2L, and NRF2 expression in human synovial cells HUM-CELL-0060, thereby confirming the association between ferroptosis and synovitis. Zhou et al (2022) showed a significant increase in levels of ACSL4 and NOX4, whereas a significant decrease in GPX4 levels was observed in cartilage of RA patients. Similar results were observed in the adjuvant arthritis (AA) rat model, indicating an association between enhancement in ferroptosis of chondrocytes and RA progression.…”

Section: Ferroptosis and Rheumatoid Arthritismentioning

confidence: 87%

“…Recently Zhou et al (2022) showed a correlation between transient receptor potential melastatin 7 (TRPM7) levels and various core regulators of ferroptosis in chondrocytes of patients with RA and the AA rat model. Knockdown of TRPM7 expression or inhibiting its activity can protect chondrocytes from ferroptosis.…”

Section: Use Of Ferroptosis-related Drugs In Rheumatoid Arthritis Tre...mentioning

confidence: 99%

Advancement in understanding the role of ferroptosis in rheumatoid arthritis

et al. 2022

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Rheumatoid arthritis (RA) is a chronic, systemic disease of unknown etiology. The primary manifestation of RA is inflammatory synovitis, which eventually leads to deformity and functional loss. Ferroptosis is a non-apoptosis form of cell death that depends on intracellular iron accumulation. This leads to an increase in reactive oxygen species (ROS) induced-lipid peroxidation. The underlying mechanisms of ferroptosis are System Xc- and Glutathione metabolism, regulation of glutathione peroxidase 4 activity, and ROS generation. Recent studies have shown an association between the pathogenesis of RA and ferroptosis, suggesting the involvement of ferroptosis in the onset and progression of RA. In this review, we have focused on the mechanism of ferroptosis and its association with RA pathogenesis. Further, we discuss the status of therapeutics targeting ferroptosis in the treatment of patients with RA. Targeting ferroptosis could be a potential therapeutic approach for RA treatment.

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“…Human chondrocytes (C28/I2 cells) at a density of 1 × 10 4 cells/well were placed on the 96-well plate, which were maintained in regular DMEM medium (Gibco, United States, Cat No. C11995) supplemented with 10% FBS (Wisent, Canada) in an air saturation of 5% CO2 at 37 °C [ 33 ]. Based on this, an in vitro models of ferroptosis was established by Erastin (ferroptosis inducer) with/without blockade of ferroptosis-related biomarkers.…”

Section: Methodsmentioning

confidence: 99%

Identification of ferroptosis related markers by integrated bioinformatics analysis and In vitro model experiments in rheumatoid arthritis

Xia

Zhang

et al. 2023

BMC Med Genomics

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Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive and symmetrical joint diseases and synovitis. This research attempted to explore the mechanisms involving ferroptosis in RA, and find the biological markers by integrated analysis. Methods Gene expression data (GSE55235 and GSE55457) of synovial tissues from healthy and RA individuals were downloaded. By filtering the differentially expressed genes (DEGs) and intersecting them with the 484 ferroptosis-related genes (FRGs), the overlapping genes were identified. After the enrichment analysis, the machine learning-based approaches were introduced to screen the potential biomarkers, which were further validated in other two datasets (GSE77298 and GSE93272) and cell samples. Besides, we also analyze the infiltrating immune cells in RA and their correlation with the biomarkers. Results With the criteria, 635 DEGs in RA were included, and 29 of them overlapped in the reported 484 FRGs. The enrichments of the 29 differentially expressed ferroptosis-related genes indicated that they may involve in the FoxO signaling pathway and inherited metabolic disorder. RRM2, validating by the external datasets and western blot, were identified as the biomarker with the high diagnostic value, whose associated immune cells, such as Neutrophils and Macrophages M1, were also further evaluated. Conclusion We preliminary explored the mechanisms between ferroptosis and RA. These results may help us better comprehend the pathophysiological changes of RA in basic research, and provide new evidences for the clinical transformation.

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TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis

Cited by 53 publications

References 49 publications

Oxygen Self-Generating Nanoreactor Mediated Ferroptosis Activation and Immunotherapy in Triple-Negative Breast Cancer

Oxygen Self-Generating Nanoreactor Mediated Ferroptosis Activation and Immunotherapy in Triple-Negative Breast Cancer

Advancement in understanding the role of ferroptosis in rheumatoid arthritis

Identification of ferroptosis related markers by integrated bioinformatics analysis and In vitro model experiments in rheumatoid arthritis

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