Pirfenidone regulates antioxidant response via NRF2 in an experimental model of hepatocellular carcinoma

Introduction and Objectives

1) Determinate if pirfenidone (PFD) modifies oxidative stress markers. 2) Evaluate PFD effects on transcription factor Nrf2 signaling pathway.

Materials and methods

Eighteen Fischer-344 rats divided into three groups were used: 1) untreated (NT), 2) carcinogenic damage (HCC) generated by weekly administration of diethylnitrosamine (50mg/kg/week;i.p.) and 2-Acetylaminofluorene (25mg/ kg/wk, p.o) and 3) HCC treated with PFD (300 mg/kg, p.o.) (HCC/PFD) for 18 weeks. Histopathological analyzes of the liver were performed, MDA and GSH levels were quantified and SOD, CAT, GSTP1 and Nrf2 expression was evaluated by Western-Blot. Data were analyzed using ANOVA and Tukey's test as post hoc. The trial was approved by the research ethics committee.

Results

In the HCC group, Nrf2, SOD, CAT, and GSTP1 expression was increased. PFD treatment was effective in preventing the increase in MDA levels and allowed GSH increase; in addition, PFD was effective in modulating the expression of Nrf2 and antioxidant response proteins.

Discussion

Oxidative stress is key in the genesis of HCC and the mechanisms leading to antioxidant response are modulated by Nrf2. PFD is an antioxidant evaluated in several liver fibrosis models. Additionally, in this work, we have demonstrated that the antioxidant response of PFD in an HCC experimental model is mediated by Nrf2.

Conclusion

PFD delays the HCC development by regulating Nrf2 signaling pathway. Clinical studies with PFD are being devised to evaluate the safety.

Funding

The resources used in this study were from the hospital without any additional financing

Declaration of interest

The authors declare no potential conflicts of interest.