1,8-Cineole improves hepatic fibrosis by inhibiting HIF-1α/BNIP3/PINK1/Parkin-dependent mitophagy signaling and inducing apoptosis in activated hepatic stellate cells.

AIM: The HIF-1α/BNIP3/mitophagy signaling pathway might be closely associated with hepatic fibrosis. Although 1,8-cineole (CIN) has been shown to improve fibrosis in several organs, direct evidence for its anti-hepatic fibrotic effects remains lacking. The objective of this study was to confirm the role of mitophagy in hepatic stellate cells (HSCs) and the role of the HIF-1α/BNIP3 signaling pathway in the pathogenesis of hepatic fibrosis. Additionally, in vivo and in vitro experiments were conducted to explore the effect of CIN on hepatic fibrosis. METHODS: In a CCl4-induced hepatic fibrosis rat model and in CoCl2-treated HSCs, expression level of HIF-1α, BNIP3, α-SMA, collagen 1, PINK1, Parkin, p62 and LC3-II/LC3-I were examined, and the ubiquitinated Parkin level was detected following immunoprecipitation. In addition, the proliferation and apoptosis of HSCs were detected. RESULTS: Our findings indicated that CIN significantly mitigated CCl4-induced hepatic fibrosis. The alleviation of hepatic fibrosis after CIN treatment was associated with a markedly decrease in HIF-1α, BNIP3, α-SMA, collagen 1, PINK1, Parkin and LC3-II/LC-I, as well as a signally increase in P62. Moreover, CIN, Mdivi-1 (mitophagy inhibitor) and Bafilomycin A1 (lysosomal inhibitors) significantly inhibited the proliferation of HSCs. The ubiquitinated Parkin level was significantly more prominent in the CoCl2 group, while the ubiquitinated Parkin level was observably decreased after CIN treatment. Additionally, CIN exhibited efficacy comparable to that of TRAIL (apoptosis-inducing agent) in significantly promoting apoptosis in hepatic stellate cells. CONCLUSION: CIN improves hepatic fibrosis by inhibiting HIF-1α/BNIP3/PINK1/Parkin-dependent mitophagy signaling and inducing apoptosis in activated HSCs.