Mitochondrial damage and post-translational modifications in radiation-induced heart disease: mechanisms and emerging therapeutic targets
Radiation-induced heart disease (RIHD) is a major late complication of thoracic radiotherapy. However, the mechanisms responsible for its long-term progression remain poorly understood. Conventional explanations, such as DNA damage, and oxidative stress, mainly focus on early radiation responses and fail to fully account for the prolonged latency and progressive myocardial remodeling observed in RIHD over years to decades. This review proposes that persistent disruption of mitochondrial homeostasis represents a central link between early radiation-induced injury and late cardiac remodeling. We systematically summarize the major processes involved in radiation-induced mitochondrial dysfunction. These processes include mtDNA damage, respiratory chain impairment, sustained mitochondrial reactive oxygen species (mitoROS) accumulation, metabolic network remodeling, and defective mitochondrial clearance through mitophagy. We further discuss how acetylation, SUMOylation, and lactylation regulate these processes and contribute to the development and progression of RIHD. Building on this framework, we highlight emerging molecular targets, including NDP52, ATP5F1C, P4HB, and SH3GLB1, as well as the potential protective effects of bioactive compounds derived from traditional Chinese medicine, such as aloe-emodin and astragaloside IV, through restoration of mitochondrial homeostasis. By integrating mitochondrial dysfunction, post-translational modifications, and mitophagy into a unified pathological framework, this review provides new perspectives for early identification and therapeutic intervention in RIHD. RIHD is not simply an oxidative stress-driven disorder but rather a chronic remodeling process shaped by the interplay among mitochondrial injury, post-translational modifications, and mitophagy dysregulation. This integrated framework links early subcellular alterations to late cardiac remodeling and provides a potential biological explanation for the long latency and progressive nature of RIHD. However, most current evidence is derived from adult models. Future research should specifically address childhood cancer survivors, as radiation exposure during critical periods of cardiac development may result in distinct long-term cardiovascular outcomes.