The anti-radiation effect of hydroxytyrosol

Hydroxytyrosol (HT), a natural phenolic antioxidant derived from Oleaceae plants, possesses strong free radical-scavenging abilities due to its rich phenolic hydroxyl groups in the structure. In the field of anti-radiation, its protective effect against DNA damage is mainly achieved through multiple mechanisms, including reducing radiation-induced oxidative stress, enhancing DNA repair capacity, and maintaining cellular redox balance, as detailed below:

I. Directly scavenging radiation-induced reactive oxygen species (ROS) to reduce DNA oxidative damage

Radiation (especially ionizing radiation) damages DNA mainly through "indirect effects": when radiation energy is absorbed by intracellular water molecules, it triggers radiolysis of water, generating a large amount of ROS, such as hydroxyl radicals (・OH), superoxide anions (O₂⁻・), and hydrogen peroxide (H₂O₂). These ROS are highly oxidizing and can directly attack DNA molecules:

Damaging base structures (e.g., oxidizing guanine to 8-hydroxydeoxyguanosine (8-OHdG), a typical marker of DNA oxidative damage);

Breaking phosphodiester bonds, leading to DNA single-strand breaks (SSB) or double-strand breaks (DSB) — improper repair of DSBs can easily cause chromosomal aberrations, gene mutations, or even cell death.

The phenolic hydroxyl groups (-OH) of hydroxytyrosol can neutralize strong free radicals such as ・OH through redox reactions by donating hydrogen atoms, terminating the oxidative chain reaction. Studies have shown that HT pretreatment can significantly reduce intracellular ROS levels after radiation exposure, decrease the production of 8-OHdG, and reduce the number of DNA strand breaks (e.g., shortened "comet tail length" observed in comet assays), thereby reducing DNA oxidative damage at the source.

II. Activating endogenous antioxidant systems to enhance cellular radiation resistance

In addition to directly scavenging ROS, hydroxytyrosol can also enhance the function of endogenous antioxidant defense systems by regulating intracellular antioxidant signaling pathways, indirectly reducing DNA damage. The most critical pathway is the Nrf2-ARE (nuclear factor erythroid 2-related factor 2-antioxidant response element) pathway:

Nrf2 is a core transcription factor for cellular antioxidant stress. Under normal conditions, it is inactivated by binding to the cytoplasmic inhibitory protein Keap1;

Hydroxytyrosol can modify the sulfhydryl groups of Keap1, releasing its inhibition on Nrf2. This allows Nrf2 to enter the nucleus, bind to the ARE sequence, and initiate the expression of downstream antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and enzymes related to glutathione (GSH) synthesis (e.g., γ-glutamylcysteine synthetase).

These enzymes and molecules can synergistically scavenge ROS, reduce oxidized products, maintain intracellular redox balance, and reduce the continuous attack of radiation-induced oxidative stress on DNA, thereby enhancing cellular resistance to radiation.

III. Regulating DNA damage repair pathways to promote accurate repair of damaged DNA

Even if DNA damage has occurred, hydroxytyrosol can accelerate damage repair by regulating repair mechanisms, reducing mutations caused by incorrect repair. Different types of radiation-induced DNA damage correspond to different repair pathways, and HT mainly affects the following key repair processes:

Base excision repair (BER): For radiation-induced base oxidation (e.g., 8-OHdG), HT can upregulate key enzymes in the BER pathway, such as DNA glycosylase (responsible for recognizing and excising damaged bases), AP endonuclease (cleaving abasic sites left by damaged bases), and DNA ligase (ligating repaired DNA strands), accelerating the removal and repair of damaged bases;

Double-strand break repair (DSB repair): DSB is the most severe form of DNA damage; improper repair can easily lead to chromosomal translocations or deletions. HT can improve the efficiency of the two main DSB repair pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). For example, it upregulates Rad51 protein in HR (mediating homologous sequence pairing) and Ku70/Ku80 complex in NHEJ (recognizing broken ends and recruiting repair enzymes), reducing the proportion of unrepaired or incorrectly repaired DSBs.

IV. Inhibiting radiation-induced inflammatory responses to alleviate secondary DNA damage

In addition to directly damaging DNA, radiation can activate intracellular inflammatory signaling pathways (e.g., NF-κB pathway) and induce the release of pro-inflammatory cytokines (e.g., TNF-α, IL-6). These cytokines further stimulate ROS production, forming an "oxidative stress-inflammation" vicious cycle that exacerbates DNA damage.

Hydroxytyrosol can reduce the expression of pro-inflammatory cytokines by inhibiting the activation of NF-κB, breaking this cycle. Meanwhile, its phenolic structure can directly inhibit the activity of inflammation-related enzymes (e.g., cyclooxygenase-2, COX-2), reducing secondary DNA damage caused by inflammatory responses and indirectly protecting DNA integrity.

Hydroxytyrosol exerts a protective effect against radiation-induced DNA damage through a multi-target mechanism: "scavenging ROS to reduce initial damage — enhancing endogenous antioxidant defense — promoting DNA damage repair — inhibiting inflammation to alleviate secondary damage". This multi-pathway synergistic effect makes it a potential radiation protectant, particularly suitable for reducing DNA damage to normal cells caused by radiation exposure (e.g., radiotherapy, occupational exposure).