Key Takeaways & Executive Findings
- •• EEPD1 deficiency exacerbates radiation-induced cardiac hypertrophy and apoptosis, while overexpression is protective. • EEPD1 directly interacts with FOXO3A and promotes its deubiquitination, leading to FOXO3A degradation. • FOXO3A inhibition reverses the detrimental effects of EEPD1 knockdown, confirming the EEPD1-FOXO3A axis as a key pathway. • This study identifies EEPD1 as a potential therapeutic target for mitigating radiation-induced heart disease.
Abstract
Radiation-induced heart disease (RIHD) is a severe delayed complication of thoracic irradiation (IR). Endonuclease/exonuclease/phosphatase family domain-containing 1 (EEPD1) plays an important role in DNA damage repair, but its role in RIHD is less known. In this study, EEPD1 global knockout mice, C57BL/6J mice, and C57BL/6J mice overexpressing EEPD1 are treated with radiation at a total dose of 20 Gy or 0 Gy. After 9 weeks, echocardiography is used to assess cardiac hypertrophy and apoptosis. The results show that EEPD1 deletion exacerbates radiation-induced cardiac hypertrophy and apoptosis, while EEPD1 overexpression has the opposite effect. Further mechanistic investigations reveal that EEPD1 interacts with FOXO3A and destabilizes it by catalyzing its deubiquitination. Inhibition of FOXO3A ameliorates cardiac hypertrophy and apoptosis after EEPD1 knockdown. Thus, EEPD1 protects against radiation-induced cardiac hypertrophy and apoptosis via destabilization of FOXO3A, which may offer new insight into therapeutic strategies for RIHD.
1. Introduction
Radiation-induced heart disease (RIHD) is a significant adverse effect of radiation therapy in the treatment of thoracic tumors, breast cancer, chest wall malignancies, and lymphoma [1]. The pathologies of RIHD are chronic progressive processes. Previous studies have shown that endothelial cell damage, especially in microvascular cells, may play an important role in RIHD [2]. Oxidative stress, the DNA damage response, telomere erosion, and mitochondrial dysfunction are also important causes of RIHD [3,4]. Despite these findings, the molecular mechanisms underlying RIHD remain incompletely understood.
In 2015, the up-regulation of endonuclease/exonuclease/phosphatase family domain-containing 1 (EEPD1) was detected in embryonic stem cells following DNA damage [5]. Moreover, several studies have revealed that EEPD1 plays a crucial role in the pathology of many diseases, including esophageal squamous cell carcinoma [6], acute myeloid leukemia [7] and breast cancer [8]. Because many of these diseases tend to occur in the thoracic region, we speculated that EEPD1 expression may be correlated with RIHD. The EEPD1 gene belongs to the ribonuclease gene family. It has been demonstrated that EEPD1 is recruited to stalled replication forks during replication stress, where it promotes their restart. Our study demonstrated the important role of EEPD1 in regulating cardiac apoptosis and hypertrophic RIHD.
A member of the FOXO subfamily, FOXO3A, was first identified in the human placental cosmid. It mediates a variety of cellular processes, including apoptosis, proliferation, cell cycle progression and DNA damage. It also responds to several cellular stresses, such as UV irradiation and oxidative stress. There is a close relationship between FOXO3A and cardiovascular diseases such as cardiac hypertrophy [9,10], cardiac ischemia/reperfusion [11], and atherosclerosis [12]. However, the role of FOXO3A in RIHD has not been explored. In this study, we found that EEPD1 expression decreases in RIHD, which enhances FOXO3A level and exacerbates cardiac hypertrophy and apoptosis. These effects are ameliorated by FOXO3A inhibition. In conclusion, the EEPD1-FOXO3A axis plays a significant role in RIHD.
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Kaiwen Yu, Xi Su, Tongfang Zhou, Xuwei Cai, Min Zhang (2026). EEPD1 attenuates radiation-induced cardiac hypertrophy and apoptosis by degrading FOXO3A in cardiomyocytes. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024130
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Frequently Asked Questions
What is the role of EEPD1 in radiation-induced heart disease?
EEPD1 protects against radiation-induced cardiac hypertrophy and apoptosis by degrading FOXO3A, thereby mitigating the detrimental effects of thoracic irradiation.
How does EEPD1 regulate FOXO3A?
EEPD1 interacts with FOXO3A and promotes its deubiquitination, leading to FOXO3A destabilization and degradation.
What are the key findings of this study?
EEPD1 deletion exacerbates radiation-induced cardiac hypertrophy and apoptosis, while overexpression is protective. FOXO3A inhibition reverses the effects of EEPD1 knockdown, confirming the EEPD1-FOXO3A axis as a critical pathway.
What is the clinical significance of this research?
This study identifies EEPD1 as a potential therapeutic target for preventing or treating radiation-induced heart disease in patients undergoing thoracic radiotherapy.
What experimental models were used?
The study used EEPD1 global knockout mice, C57BL/6J mice, and C57BL/6J mice overexpressing EEPD1, all subjected to cardiac irradiation at a total dose of 20 Gy or 0 Gy.
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