Targeting <scp>DNMT1</scp> Attenuates Radiation‐Induced Heart Disease: An Integrated Multiomic and Functional Study

Radiation-induced heart disease (RIHD) is a serious adverse reaction after tumor radiotherapy; its molecular mechanism is not yet clear, and there is a lack of effective treatment strategies. DNA methyltransferase 1 (DNMT1) plays crucial roles in various biological processes, but its function in RIHD remains to be explored. This study aimed to systematically elucidate the molecular map of RIHD using multiomic methods, with a focus on the specific functions and mechanisms of DNMT1 in the development of RIHD. In this study, in vivo and in vitro models of radiation-induced cardiac injury were constructed. Changes in molecular expression in cardiac tissues and cells caused by radiation were systematically analyzed through techniques such as transcriptomics and proteomics. Adeno-associated virus and lentivirus transfection techniques were used to knock down Dnmt1 expression to explore its functional role in RIHD. Multiomic analysis revealed significant activation of immune/inflammatory responses and metabolic disorders in RIHD. X-ray irradiation induced myocardial tissue and cell damage and inhibited PI3K/PDK1/AKT signaling. Moreover, radiation significantly upregulated the expression of DNMT1 in myocardial tissue and cells. Dnmt1 knockdown alleviated radiation-induced myocardial tissue and cell damage and partially reversed the inhibition of PI3K/AKT signaling. In addition, 15 proteins directly interacting with DNMT1 were identified by CO-IP and GST-pulldown assays combined with mass spectrometry, suggesting that these proteins may participate in the development of RIHD through a variety of molecular mechanisms. The results of this study revealed that DNMT1 plays a role in promoting disease progression by regulating the PI3K/AKT signaling pathway in RIHD. These findings provide a new perspective for understanding the pathogenesis of RIHD and suggest that DNMT1 may serve as a potential target for therapeutic interventions. Therefore, DNMT1 represents a promising therapeutic target for preventing RIHD.