Hsa_circ_0001944 Regulates FXR/TLR4 Pathway and Ferroptosis to Alleviate Nickel Oxide Nanoparticles-Induced Collagen Formation in LX-2 Cells.

Nickel oxide nanoparticles (NiONPs) can induce liver fibrosis, and their mechanism may be related to non-coding RNA, nuclear receptor signal transduction and ferroptosis, but the regulatory relationship between them is not clear. In this study, we aimed to investigate the role of hsa_circ_0001944 in regulating the Farnesol X receptor (FXR)/Toll-like receptor 4 (TLR4) pathway and ferroptosis in NiONPs-induced collagen deposition. We observed decreased FXR expression, increased TLR4 expression and alterations in ferroptosis features in both the rat liver fibrosis and the LX-2 cell collagen deposition model. To investigate the regulatory relationship among FXR, TLR4 and ferroptosis, we treated LX-2 cells with FXR agonist (GW4064), TLR4 inhibitor (TAK-242) and ferroptosis agonist (Erastin) combined with NiONPs. The results showed that TAK-242 alleviated collagen deposition by increasing ferroptosis features. Furthermore, GW4064 reduced the expression of TLR4, increased the ferroptosis features and alleviated collagen deposition. The results indicated that FXR inhibited the expression of TLR4 and enhanced the ferroptosis features, which were involved in the process of collagen deposition in LX-2 cells induced by NiONPs. Subsequently, we predicted that hsa_circ_0001944 might regulate FXR through bioinformatics analysis, and found NiONPs reduced the expression of hsa_circ_0001944 in LX-2 cells. Overexpression of hsa_circ_0001944 increased FXR level, reduced TLR4 level, increased the ferroptosis features and alleviated collagen deposition in LX-2 cells. In summary, we demonstrated that hsa_circ_0001944 regulates the FXR/TLR4 pathway and ferroptosis alleviate collagen formation induced by NiONPs.