Radioprotection or radiosensitization? Unraveling caffeine’s bifurcated effects on radiation-induced damage

Caffeine, a widely consumed phytochemical, exhibits a dual and paradoxical role in modulating cellular responses to radiation, acting as both a radioprotector and radiosensitizer depending on context. This comprehensive review synthesizes evidence from <i>in vitro</i>, <i>in vivo</i>, and clinical studies to elucidate caffeine's multifaceted interactions with ionizing (gamma rays, X-rays) and non-ionizing (UV) radiation. Mechanistically, caffeine influences DNA repair pathways-notably inhibiting ATM/ATR checkpoint kinases-overrides G2/M cell cycle arrest, and modulates apoptosis through p53-dependent and independent pathways. While caffeine demonstrates radioprotective potential by mitigating oxidative stress, enhancing antioxidant defenses, and reducing chromosomal aberrations in normal tissues, it concurrently sensitizes cancer cells to radiation by disrupting DNA repair and amplifying mitotic catastrophe. Intriguingly, its effects vary by radiation type, dose, cell lineage (e.g. p53 status), and administration timing, underscoring its context-dependent utility. Preclinical studies highlight caffeine's capacity to attenuate radiation-induced hepatotoxicity, skin damage, and cataract formation, yet caution is warranted due to risks of exacerbating chromosomal instability and teratogenicity. Clinically, retrospective data suggest caffeine may reduce late radiotherapy toxicity in cervical cancer patients, though evidence remains sparse. This review underscores caffeine's potential as an adjuvant in radiotherapy but emphasizes the necessity for precision in its application, balancing therapeutic benefits against risks. Further research is critical to unravel dose-response dynamics, optimize timing, and validate clinical translatability across diverse radiation modalities.