PAX6 contributes to the activation and proliferation of hepatic stellate cells via activating Hedgehog/GLI1 pathway

Aberrant activation of Hedgehog signaling is considered as the key player in hepatic stellate cell (HSC) activation involved in liver fibrosis (LF). The glioma-associated protein gene (Gli) has a predicted paired box 6 (PAX6)-binding site within its transcribed region. Therefore, this study aimed to investigate the relationship between PAX6 and Gli and their contribution to HSC activation and proliferation. PAX6 expression was upregulated in platelet-derived growth factor-BB (PDGF-BB)-induced LX-2 cells. The activation and proliferation of HSC were inhibited by interference of PAX6 with short hairpin RNA (shPAX6) via curbing Hedgehog signaling. Notably, PAX6 directly bound to the promoter sequence of GLI1 independent of the PTCH/Smo axis. Therefore, we propose that PAX6 upregulation induces HSC activation and proliferation through crosstalk with GLI1 signaling. Thus, these novel mechanistic insights involving the PAX6-mediated regulation of the activation and proliferation of HSC may provide a new therapeutic target for LF.