Caffeic acid activates Nrf2 enzymes, providing protection against oxidative damage induced by ionizing radiation

Caffeic acid (CA) is a prevalent polyphenolic compound commonly found in various plant-derived foods. Due to its diverse pharmacological properties, including antioxidant activity, cardiovascular protection, and immune regulation, CA has garnered significant attention. Ionizing radiation (IR) is extensively utilized across industrial sectors, agriculture, defense applications, scientific research, and clinical medicine; however, the detrimental effects of radiation on human health cannot be ignored. IR can directly damage the DNA, proteins, and lipids within macromolecules or ionize water molecules to generate substantial quantities of free radicals that indirectly harm cells, especially those in the brain which are highly susceptible to radiation exposure. Consequently, effective strategies for preventing and treating IR-induced neurological damage represent an urgent medical challenge that necessitates resolution. Our study aims to investigate the protective effects of CA against IR-induced neuronal cell damage along with elucidating its potential mechanisms of action. The results indicate that CA can covalently modify active cysteine residues on Keap1 protein altering its conformation; this modification disrupts the interaction between Keap1 and Nrf2 while facilitating Nrf2's translocation into the nucleus where it activates downstream expression of cellular protective factors such as heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1), Thioredoxin Reductase-1 (TrxR1) and other cellular protective factors to play a role in countering radiation-induced neurological damage. In conclusion, CA emerges as an effective radioprotective agent capable of exerting antiradiation effects. Our findings provide valuable insights for developing novel therapeutic agents aimed at preventing and treating IR-induced neurological impairment.