DNA methylation patterns re-establish during clonal expansion restoring cell-to-cell epialleles heterogeneity.

IR induces injury in many tissues and organs. IR directly leads to abnormal cell function and metabolic disorders through its destructive effect on the molecular structure of cells. It also indirectly leads to DNA damage and further increases in cellular free radical levels through the production of free radicals and radiolytic decomposition of water. [-]. The damage by high-dose IR to biological macromolecules is fatal, and can lead to death within a short time, and the attack on DNA by the free radicals is the main cause of death at low and moderate radiation doses [, ]. RIHD is a growing clinical problem seen in cancer patients treated with thoracic radiotherapy and/or genotoxic chemotherapies. This disease comprises a wide spectrum of disorders, often with long latency periods between IR exposure and clinical presentation, requiring consistent follow-up and screening. Side effects of IR on the heart include pericarditis, CAD, arrhythmias, cardiomyopathy, valvular dysfunction, and heart failure. Pericarditis and pericardial effusions are potential short-term toxicities that may occur during or within the weeks following IR [, ]. There are several mechanisms involved in the induction of cardiotoxicity due to IR exposure in cancer patients, one of which is oxidative stress [, ]. In oxidative stress, an imbalance between the production of ROS and its removal by the antioxidant defense system mediates damage to the structure of cellular macromolecules, including lipids, proteins, and DNA [, ]. ROS generated during radiation exposure play a central role in the development of tissue fibrosis. Excess ROS cause oxidative damage to cellular structures, including DNA, lipids, and proteins, leading to activation of fibrogenic signaling pathways such as TGF-β. This promotes the transdifferentiation of fibroblasts into myofibroblasts, which produce excessive extracellular matrix components, resulting in tissue stiffening and fibrosis. Therefore, oxidative stress driven by ROS is a key mechanistic mediator in radiation-induced tissue remodeling and fibrosis [, ]. Oxidative stress and chronic and acute overproduction of ROS have always been considered to be important pathophysiological mediators leading to CVD [, ]. Radiosensitizers and radioprotectors have shown the potential to mitigate cardiotoxicity and tissue damage during TBI. These agents can either boost radiation's effectiveness on tumors or safeguard healthy tissues from radiation-related damage, leading to better patient outcomes [, ]. However, few of these compounds have clear efficacy and superior performance. Researchers have shown that PGZ administration can significantly reduce radiation-induced ROS production and increase antioxidant enzyme activity, thereby regulating cell-protective proteins in cardiac tissue [, ]. In addition, PGZ modulates proinflammatory cytokines and signaling cascades with anti-inflammatory properties, which may help reduce the inflammatory response associated with radiation injury to the heart []. Moreover, numerous studies have demonstrated the cardioprotective effects of PGZ in various experimental models. It exerts its protective effects primarily through activation of the PPARγ, which regulates gene expression related to metabolism, inflammation, and fibrosis. Activation of PPARγ by PGZ leads to downstream signaling involving the MAPK pathway, particularly ERK1/2, which promotes cell survival and reduces apoptosis. Additionally, PGZ modulates inflammatory mediators by decreasing cyclooxygenase-2 (COX-2) expression. Its ability to reduce oxidative stress and inflammatory responses helps limit tissue damage and fibrosis in the myocardium, thereby improving overall cardiac function [, ]. These data suggest that the antioxidant and anti-inflammatory effects of PGZ can be used to protect against heart injury induced by ionizing radiation, which is potentially beneficial for patients undergoing IR or those injured in nuclear accidents. The detrimental effects of IR on the heart can be acutely apparent in the first week or delayed after several weeks or months. Acute radiation-induced cardiac damage is characterized by oxidative stress, inflammation, and structural changes, while delayed effects can lead to long-term complications such as fibrosis and impaired cardiac function. Evaluating the radioprotective potential of pharmacological interventions at the early and delayed stages is crucial to fully understanding their efficacy in mitigating the multifaceted cardiac complications associated with radiation exposure. According to the above, PGZ may contribute to its potential radioprotective effects in the heart by effectively suppressing oxidative stress and inflammation, two key pathways underlying the detrimental effects of ionizing radiation exposure. In this study, we investigated the ability of PGZ, with potent antioxidant and anti-inflammatory properties, to protect the heart against RIHD one week and one month after X-ray