Work

ATF3 enhancement of CHAC1 expression: A pathway to neuronal ferroptosis in spinal cord injury

Year: 2025

Type: article

Abstract: Spinal cord injury (SCI) is a crippling neurological disorder with few therapies. Recent findings show that ferroptosis, an iron-dependent form of programmed cell death, is critical to SCI. This study looks at how activating transcription factor 3 (ATF3) promotes neuronal ferroptosis via cation transport regulator 1 (CHAC1) in SCI mice. C57BL/6JNifdc mice were utilized to establish an SCI model through contusion injury. The expression and implications of ATF3 and CHAC1 were explored using immunofluorescence, Terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining, and quantitative real-time polymerase chain reaction (qRT-PCR). VSC4.1 motor neuron cells injury was induced by H 2 O 2 and employed to further delineate the pathway in vitro , with treatments including siRNA-mediated ATF3 silencing and CHAC1 overexpression. Cell apoptosis and cloney-forming ability were assessed by flow cytometry and colony formation assay. And specific kits were used to detect ferroptosis indicators such as lipid peroxidation, glutathione (GSH) levels, and iron accumulation. The expressions of nuclear factor-erythroid 2 related factor 2 (NRF2) and glutathione peroxidase 4 (GPX4) were detected by western blot. Ferroptosis of neuron cells occurred in SCI mice. ATF3 was significantly upregulated in SCI mice, correlating with increased CHAC1 expression and enhanced neuronal ferroptosis markers. In vitro , ATF3 knockdown reduced ferroptosis and improved cell survival, while CHAC1 overexpression negated these effects, highlighting a critical interaction in ferroptosis regulation. ATF3 enhances CHAC1 expression to promote neuronal ferroptosis in SCI, suggesting that targeting this pathway could offer a novel therapeutic strategy for SCI recovery. • SCI model mice showed neurone cell ferroptosis, which Fer-1 reversed. • Overexpression of CHAC1 reversed si-ATF3 regulation in H 2 O 2 -treated VSC4.1 cells. • ATF3 promoted SCI by up-regulating CHAC1.

Source: Brain Research Bulletin

DOI: 10.1016/j.brainresbull.2025.111568

Authors: Chongwen Wang, Congdi Liu, Jialun Wang, Yongjie Ye, Zhi Zhang

Institution: Chengdu Fifth People's Hospital

Language: English

Topic: Ferroptosis and cancer prognosis

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,280