The Emerging Role of tRNA-Derived Small RNAs (tsRNAs) in Radiation-Induced Cardiovascular Pathology

Ionizing radiation exposure during thoracic radiotherapy is a risk factor for long-term cardiovascular morbidity, including radiation-induced heart disease (RIHD). Emerging evidence implicates transfer RNA-derived small RNAs (tsRNAs) as stress-responsive regulatory molecules, yet their roles in RIHD remain unexplored.

A comprehensive literature review was conducted to explore tsRNA biology, radiation- induced cardiovascular injury, and non-coding RNA function. We systematically searched databases including PubMed, Web of Science, and Scopus using keywords such as "tsRNA," "tRNA- derived fragments," "radiation-induced heart disease," "oxidative stress," and "cardiovascular injury." Literature screening prioritized original research articles and high-impact reviews providing mechanistic insights into tsRNA expression, biogenesis, or function in the context of radiation response or cardiovascular pathologies. Non-peer-reviewed articles, conference abstracts, non- English publications, or studies not directly relevant to the core themes were excluded. The selected studies were analyzed to identify and synthesize the mechanistic links between tsRNA dysregulation and radiation-induced cardiovascular damage.

Ionizing radiation robustly induces tsRNA biogenesis via endonucleases (e.g., angiogenin, Dicer) in cardiovascular cells. Post-irradiation, specific tsRNAs are dysregulated and contribute to key RIHD mechanisms, including sustained oxidative stress, mitochondrial dysfunction, endothelial senescence, DNA damage response, and fibrotic remodeling. These tsRNAs modulate critical signaling pathways, including PI3K/AKT, JNK, and NF-κB, thereby regulating targets involved in redox balance, apoptosis, and extracellular matrix deposition. Notably, circulating tsRNAs emerge as promising early, non-invasive biomarkers of radiation exposure in both preclinical and clinical settings, highlighting their translational potential.

Our study reveals that tsRNAs serve as molecular transducers linking acute radiation stress to chronic cardiovascular dysfunction. Further, they hold promise as early warning biomarkers and therapeutic targets in cardio-oncology.

Radiation-induced cardiovascular disease is pathologized by tsRNAs. They identify potential non-invasive biomarkers to detect RIHD early and possibly target it for treatment in cancer survivors.