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·Life Sciences

Melatonin protects against particulate matter-induced ovarian dysfunction by activating the Nrf2 signaling pathway to alleviate ferroptosis

Article

Author: Zhu, Laiyu ; Man, Xiaxia ; Chen, Lu ; Ci, Xinxin ; Yu, Xiaowei ; Zhang, Qi ; Zhang, Xiaoyuan ; Zhu, Chao

Accumulating evidence suggests that exposure to ambient airborne PM2.5 increases the risk of primary ovarian insufficiency (POI). However, whether ferroptosis, a newly discovered type of cell death involved in PM2.5-induced lung injury and fibrosis, is involved in PM2.5-induced POI has not been determined. This study aimed to verify the involvement of PM2.5-induced ferroptosis in ovarian dysfunction and further demonstrate that melatonin inhibits ferroptosis by activating the Nrf2 signaling pathway to ameliorate POI in vivo and in vitro. In our study, PM2.5 promoted iron accumulation and induced lipid peroxidation, thus contributing to ferroptosis in KGN cells and ovaries. However, these effects were eliminated and enhanced in Nrf2-overexpressing and Nrf2-knockdown cells, respectively. In addition, melatonin and ferrostatin-1 (Fer-1) inhibited ferroptosis by activating the NRF2 signaling pathway, as evidenced by the silencing of Nrf2 in vivo and in vitro. Mechanistically, Nrf2-knockout mice were more susceptible to ferroptosis and PM2.5-induced POI than control mice. Moreover, melatonin suppressed changes in morphological and biochemical indicators related to ferroptosis, such as MDA and GSH depletion and GPX4 and XCT downregulation, by enhancing Nrf2 signaling. Here, we first reported that PM2.5 triggered ferroptosis by increasing ROS levels, lipid peroxidation and glutathione depletion. Notably, melatonin significantly decreased ferroptosis levels and improved ovarian function by activating the NRF2 signaling pathway in vivo and in vitro.

01 Dec 2024·International Journal of Biological Macromolecules

1α,25-hydroxyvitamin D3 alleviated rotavirus infection induced ferroptosis in IPEC-J2 cells by regulating the ATF3-SLC7A11-GPX4 axis

Article

Author: Niu, Lili ; Wang, Yan ; Lan, Qingyuan ; Zhao, Ye ; Shang, Pan ; Zhu, Xiaoxiao ; Song, Lei ; Chen, Lei ; Zhu, Li ; Gan, Mailin ; Shen, Linyuan ; Wei, Ziang ; Hu, Shijie

Rotavirus (RV) mainly infects mature intestinal epithelial cells and impairs intestinal absorption function, which leads to the death of infected cells and eventually fatal diarrhea. Ferroptosis is a novel regulatory cell death pattern, which can be caused by virus infection. 1α,25-hydroxyvitamin D₃ (1,25D₃) has an anti-RV infection effect and can regulate ferroptosis. However, whether RV infection can induce ferroptosis, and whether 1,25D₃ can inhibit RV infection by regulating ferroptosis has not yet been studied. Present study shows that RV infection or erastin treatment induces IPEC-J2 cell death, which results in mitochondrial shrinkage, decreased mitochondrial membrane potential (MMP) and glutathione (GSH) content, increased MMP, intracellular Fe²⁺, reactive oxygen species (ROS), and malondialdehyde (MDA) contents. Meanwhile, ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), and deferoxamine (DFO) treatment can effectively reverse the increase of intracellular Fe²⁺, ROS and MDA levels induced by RV infection. Moreover, RV infection increases activating transcription factor 3 (ATF3) mRNA and protein expressions, and inhibited SLC7A11 and glutathione peroxidase 4 (GPX4) expressions, which was partially alleviated by siATF3. 1,25D₃ treatment significantly eliminates RV induced ferroptosis via ATF3-SLC7A11-GPX4 axis. Therefore, our results reveals that RV infection induces ferroptosis in IPEC-J2 cell and 1,25D₃ alleviates RV induced ferroptosis by regulating the ATF3-SLC7A11-GPX4 axis.

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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

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