NRG-1/ErbBs signaling confers cardioprotection in X-ray-irradiated rat myocardium

Background: Radiotherapy (RT) is a cornerstone of cancer treatment alongside surgery. However, thoracic RT carries a substantial risk of Radiation-Induced Heart Disease (RIHD), characterized by acute activation of inflammatory pathways that evolve into chronic pathological cascades. This study aimed to elucidate the molecular mechanisms underlying cardiac responses to irradiation, with the goal of establishing a theoretical basis for RIHD prevention and providing new insights for further investigation. Methods: DNA damage in cardiomyocytes after irradiation was assessed by immunofluorescence. Cell proliferation was evaluated using the CCK-8 assay, while apoptosis and cell cycle distribution were analyzed by flow cytometry. Protein expression levels of NRG-1, ErbB4, ErbB2, and p53 were detected by Western blotting. Serum cardiac injury biomarkers were quantified by enzyme-linked immunosorbent assay (ELISA). Myocardial inflammation and fibrosis were evaluated histologically using hematoxylin and eosin (H&E) staining and Masson's trichrome staining. Results: X-ray irradiation induced significant DNA damage, cell cycle arrest, apoptosis, inflammatory activation, and p53 upregulation in cardiomyocytes. In parallel, irradiation suppressed the NRG-1/ErbB4/ErbB2 signaling pathway, thereby reducing proliferation. Histological analysis confirmed that irradiation promoted myocardial inflammation and fibrosis. The overexpression of NRG-1 conferred cardioprotection after radiation by mitigating DNA damage, facilitating cell cycle progression, and inhibiting apoptosis and inflammation, accompanied by the suppression of p53 and induction of ErbB4/ErbB2 expression. Serum cardiac injury biomarkers in irradiated rats exhibited a significant dose-dependent elevation following thoracic RT. Conclusion: The NRG-1/ErbBs signaling pathway mitigates p53 activation and, through this mechanism, promotes DNA repair, facilitates cell cycle progression, inhibits apoptosis, and reduces inflammation. Collectively, these effects enhance cardiomyocyte proliferation and confer cardioprotection against radiation-induced injury.