Activation of imidazoline I1 receptor by moxonidine regulates the progression of liver fibrosis in the Nrf2-dependent pathway.

Imidazoline I1 receptor (I1R) has been recognized as a promising target in the treatment of many diseases, but little is known about its function in liver fibrogenesis. This study aimed to investigate the effect of I1R activation on the development and progression of liver fibrosis. The results showed that I1R expression was decreased in the livers of both patients and mice with liver fibrosis, and in TGF-β-treated hepatic stellate cells (HSCs). Activation of I1R by moxonidine (MOX) significantly inhibited the progression of liver fibrosis in carbon tetrachloride-induced mice and attenuated the activation of HSCs and kupffer cells. MOX also suppressed the activation of TLR4/NF-κB and TGF-β/Smad signaling, however, knockdown of I1R abrogated the inhibitory effects of MOX. Additionally, MOX activated Nrf2 signaling in vivo and in vitro, but knockout or knockdown of Nrf2 ameliorated the anti-inflammatory and anti-fibrotic effects of MOX. Taken together, activation of I1R negatively regulates the progression of liver fibrosis in the Nrf2-dependent pathway, which suggests that specifically targeting I1R may be a potential therapeutic strategy for the treatment of liver fibrosis.