Nrf2-dependent hepatoprotective effect of ellagic acid in titanium dioxide nanoparticles-induced liver injury.

BACKGROUND AND AIMS

Previous studies suggest that titanium dioxide nanoparticles (TiO NPs) induce liver injury, possibly due to oxidative stress and inflammation. Ellagic acid (EA) is a dietary polyphenol extracted from natural sources and possesses antioxidant and anti-inflammatory properties. Nonetheless, the efficacy of EA in mitigating liver injury induced by TiO NPs remains to be elucidated.

METHODS

Primary hepatocytes and L02 cells were cultured with 45 μM EA and 10 μg/ml TiO NPs. Mice were orally administered TiO NPs (150 mg kg) and EA (25/50/100 mg kg) for eight weeks. sulforaphane (SFN) as a positive control to evaluate the inhibitory effect of EA on TiO NP-induced liver injury (SFN 10 mg kg). RNA sequencing (RNA-seq) was employed to elucidate the mechanisms underlying oxidative stress, inflammation, and liver fibrosis.

RESULTS

We assessed the impact of EA on cytotoxicity, oxidative stress, inflammation, and fibrosis in both cells and mice exposed to TiO NPs for an extended period. Our findings indicated that EA had a protective effect on TiO NP-exposed hepatocytes, reducing cytotoxicity, oxidative stress, and inflammation. Furthermore, EA treatment markedly reduced serum aminotransferase levels in mice exposed to TiO NPs. Furthermore, EA treatment notably reduced hepatic stress response, inflammation, and fibrosis in mice. The treatment of EA demonstrates non-inferiority compared to SFN. The protective effects of EA were attributed to the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), EA promoted the translocation and phosphorylation of Nrf2, as indicated by the finding that Nfe2l2 shRNA and inhibition of Nrf2 by ML385 reversed the EA-induced hepatoprotective effects in TiO NP-exposed hepatocytes and mice.

CONCLUSION

EA significantly mitigated liver injury induced by TiO NPs. Importantly, we identified that the nuclear translocation and phosphorylation of Nrf2 are the primary mechanisms through which EA alleviates liver injury resulting from exposure to TiO NPs. As a natural activator of Nrf2, EA emerges as a promising therapeutic candidate for treating TiO NPs-induced liver injury, further enhancing our understanding of its potential as a hepatoprotective agent and its underlying molecular mechanisms.