Investigating the molecular mechanism of the PI3K/AKT/Cdkn1a/GPX4 signaling axis in regulating radiation-induced cardiomyocyte ferroptosis using multi-omics and cellular models
10.13491/j.issn.1004-714X.2025.06.002
- VernacularTitle:基于多组学与细胞模型探究PI3K/AKT/Cdkn1a/GPX4信号轴调控放射性心肌细胞铁死亡的分子机制
- Author:
Yuqi SUN
1
;
Jiaming LAI
2
;
Hao CAI
3
;
Guoquan LI
2
Author Information
1. Department of Basic Medical Sciences, Qinghai University Medical College, Xining 810016, China.
2. Department of Basic Medical Sciences, Qinghai University Medical College, Xining 810016, China;Qinghai Provincial People’s Hospital, Xining 810007, China.
3. Fifth People’s Hospital/Cancer Hospital of Qinghai Province, Xining 810007, China;Department of Basic Medical Sciences, Qinghai University Medical College, Xining 810016, China.
- Publication Type:OriginalArticles
- Keywords:
Cdkn1a gene;
Radiation-induced heart disease;
PI3K/AKT signaling pathway;
GPX4;
Ferroptosis
- From:
Chinese Journal of Radiological Health
2025;34(6):789-799
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate whether the PI3K/AKT/Cdkn1a/GPX4 signaling axis participates in the pathogenesis of radiation-induced heart disease (RIHD) through the ferroptosis pathway. Methods An RIHD mouse model was established by irradiating C57BL/6J mice with 20 Gy X-rays. Transcriptomic sequencing, the FerrDb ferroptosis-related gene set, and weighted gene co-expression network analysis were used to identify hub genes associated with ferroptosis in RIHD. KEGG enrichment analysis was employed to determine key signaling pathways. An AC16 cardiomyocyte model of RIHD was constructed, and the optimal modeling conditions were determined using CCK-8 assays and flow cytometry. Reverse transcription-quantitative PCR and Western blotting were applied to validate the expression changes of key genes and pathways in cardiomyocytes. Results Compared with the control group, myocardial tissues from irradiated mice exhibited typical RIHD pathological alterations, including structural disorganization and degeneration. Bioinformatics analysis identified Cdkn1a and Ddit4 as potential hub genes, with the PI3K/AKT pathway as the key signaling pathway. The optimal conditions for establishing the RIHD cell model were determined to be 10 Gy irradiation and 48 hours of incubation. Cellular experiments confirmed that, compared with the control group (0 Gy), irradiated cardiomyocytes (10 Gy) showed significantly elevated CDKN1A expression (P < 0.01), inhibited phosphorylation of the PI3K/AKT signaling pathway (P < 0.05), downregulated GPX4 expression (P < 0.05), and induction of ferroptosis. Conclusion This study preliminarily clarifies the potential role of the PI3K/AKT/Cdkn1a/GPX4 signaling axis in regulating ferroptosis in RIHD cardiomyocytes, providing new therapeutic targets and strategies for the prevention and treatment of RIHD.
