Recent findings underscore the significance of ferroptosis, an innovative iron-dependent mode of cell death, in the etiology and progression of chronic kidney disease (CKD). Nucleophosmin 1 (NPM1), a nucleolar protein, contributes to fibrogenesis and modulates cellular functions and mortality. Initial investigations utilized bioinformatics techniques to pinpoint genes with altered expression in CKD and to forecast the potential links between NPM1, ferroptosis, and renal fibrosis. Increased NPM1 expression was verified in the renal tissues of CKD patients. Experimental models of renal fibrosis in both animals and cells were then used for further study. The suppression of NPM1 led to an augmentation in iron metabolism and lipid peroxidation processes integral to ferroptosis, contributing to the mitigation of renal fibrosis. In contrast, an elevation in NPM1 expression had the opposite effect. This modulation may be interconnected with the nuclear factor erythroid 2-related factor 2 pathway. Moreover, the application of the ferroptosis inhibitor, Fer-1, not only obstructed ferroptosis but also diminished NPM1 expression, which, in turn, contributed to the alleviation of renal fibrosis. Thus, our findings suggest that in CKD the NPM1 level increased and led to decreased ferroptosis and aggravated renal fibrosis via an Nrf2 pathway. Ferroptosis inhibitor can alleviate renal fibrosis.

01 Dec 2024·Biochemical and Biophysical Research Communications

HMGA2 regulates GPX4 expression and ferroptosis in prostate cancer cells

Article

Author: Hwang, Bor-Jang ; Awolowo, Mojisoluwa ; Odero-Marah, Valerie ; Elliott, Bethtrice ; Campbell, Taaliah ; Dike, Precious Elechi

Prostate cancer (PCa) remains a significant global health burden and an increase in oxidative stress is associated with cancer progression. High Mobility Group A2 (HMGA2), a chromatin architectural protein, increases oxidative stress and promotes sensitivity to ferroptosis inducers, however, the mechanism is unknown. We investigated the role of HMGA2 in GPX4 regulation and the impact on cellular responses to oxidative stress and ferroptosis sensitivity. We conducted UALCAN database analysis, western blot analysis, and lipid peroxidation assays to determine the relationship between HMGA2 and GPX4 and the levels of lipid reactive oxygen species in a panel of PCa cell lines, including an enzalutamide-resistant cancer cell line (C4-2B MDVR). Our results show an inverse relationship between HMGA2 and GPX4 expression with high HMGA2 and low GPX4 expression associated with higher Gleason score and lower survival probability in prostate adenocarcinoma (PRAD) patients, while low/moderate HMGA2 expression is positively associated with increased GPX4 expression and higher survival probability. Cell lines showed a moderately negative but not statistically significant correlation between HMGA2 and GPX4 expression, however, PC3 and DU145 PCa cells display higher lipid peroxides concomitant with higher endogenous levels of HMGA2 and low GPX4. Overexpression of wild-type HMGA2 in LNCaP and 22Rv1 cells leads to higher HMGA2 expression compared to Neo control and is associated with higher SLC7A11 and GPX4 expression, while interestingly truncated HMGA2 overexpression in LNCaP and 22Rv1 cells coincides with higher HMGA2 and reduced GPX4 expression, leading to increased lipid peroxides and susceptibility to ferroptosis. Overexpression of wild-type and truncated HMGA2 in 22Rv1 cells increases SLC7A11 mRNA yet differing GPX4 protein expression suggests posttranslational regulation of GPX4. Moreover, enzalutamide-resistant C4-2B MDVR cells display higher HMGA2 levels compared to C4-2B cells, as well as sensitivity to RSL3 ferroptosis inducer, which is partially reversed by ferroptosis inhibitor, ferrostatin-1. Interestingly, GPX4 expression is higher in C4-2B MDVR cells compared to C4-2B, and HMGA2 knockdown further increases its expression but does not significantly alter its susceptibility to ferroptosis. In conclusion, our study shows that HMGA2 regulation of GPX4 expression is complex and truncated HMGA2 downregulates GPX4 and increases lipid peroxides. Moreover, HMGA2-expressing cells including enzalutamide-resistant cells are susceptible to RSL-3-induced ferroptosis. Thus, ferroptosis sensitivity offers promising insights for the development of targeted therapeutic interventions for aggressive PCa.

01 Dec 2024·Biochemical and Biophysical Research Communications

Network pharmacology, molecular docking and experimental study on the mechanism of Curcumin's anti-ferroptosis in melanocytes

Article

Author: Huang, Jun-Kai ; Luo, Jing ; Yuan, Jin-Xiang ; He, Si-Jia ; Yuan, Jin-xiang ; Huang, Jun-kai ; Yuan, Chuan-jian ; Liu, Lyu-ye ; He, Si-jia ; Zhang, Jun-Ling ; Zhang, Jun-ling ; Yuan, Chuan-Jian ; Liu, Lyu-Ye

Ferroptosis is a form of regulated nonapoptotic cell death associated with iron-dependent lipid peroxidation, closely associated with Vitiligo. Although the impact of Curcumin (Cur), a polyphenolic compound derived from the plant Curcuma longa Linn, on vitiligo has been established, the specific role and potential mechanistic pathways through which Cur modulates ferroptosis in vitiligo remain elusive. In this study, the critical targets and potential mechanisms of Cur in treating vitiligo were predicted by network pharmacology and molecule docking. Then, the effects of Cur on Erastin-induced ferroptosis were investigated in melanocytes induced by Erastin in vitro. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of Cur acting on Vitiligo found that these intersection genes are associated with the vitiligo oxidative stress pathway, including nuclear factor erythroid 2-related factor 2(Nrf2)/Heme Oxygenase 1(HO-1) signaling pathway. Further molecular docking shows that Cur has a good binding effect with Nrf2(the binding energy of Cur and Nrf2 protein is -6 kcal/mol). Through the CCK8 assay, showed that 10 μM Cur treatment 24 h after Erastin significantly improved cell viability In vitro. Then we found that Erastin induced cell death, ROS production, the mitochondrial membrane potential(MMP) decreased, Superoxide dismutase (SOD) and Glutathione (GSH) levels reduced, Malonaldehyde (MDA) and iron ion accumulation in melanocytes. In addition, the expression of glutathione peroxidase 4(GPX4) mRNA and protein was inhibited, while the expression of acyl-CoA synthetase long-chain family member 4(ACSL4), Transferrin Receptor Protein 1(TFR1) mRNA and protein was increased. However, the damage induced by Erastin was signiﬁcantly relieved by Cur and Fer-1 treatment. Mechanistically, Cur treatment significantly promoted nuclear translocation of transcriptional factor Nrf2 and HO-1 expression. Interestingly, pretreatment with ML385, a selective Nrf2 inhibitor, counteracted anti-ferroptosis effects induced by Cur treatment. Taken together, these results demonstrate that Cur inhibits ferroptosis by regulating the Nrf2/HO-1 pathway to protect melanocytes.

100 Deals associated with Ferrostatin-1

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Cognitive Dysfunction	Preclinical	CN	Zhejiang University	01 Aug 2024
Neuroinflammation	Preclinical	CN	Zhejiang University	01 Aug 2024
Obstetric Labor, Premature	Preclinical	CN	Zhejiang University	01 Aug 2024
Liver transplant rejection	Preclinical	CN	Tianjin Medical University	02 Feb 2024

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

Ferrostatin-1

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation