PXDN knockdown alleviates hepatic stellate cell activation by regulating GPX1.

The central mechanism of cholestatic liver fibrosis (CLF) is the accumulation of extracellular matrix caused by the activation of hepatic stellate cells (HSCs), which is reversible in the early to mid-stages. Therefore, this study characterized the underlying molecular mechanisms involved. In this study, the liver and spleen indexes of the CLF model markedly increased and continued to rise over time. There were significant differences in ALP, TBIL, AST, DBIL, ALT, IBIL, AST/ALT, and GGT levels among rats in the CLF and SHAM groups at different time points. Histological staining revealed that the CLF had progressed to cirrhosis by week 5. Importantly, relative to the SHAM group, the CLF-2, CLF-3, CLF-4, and CLF-5 groups contained 2886, 3472, 5297, and 4586 differentially expressed genes (DEGs), respectively. The four comparisons identified 1848 shared DEGs that regulate cell growth, chemotaxis, inflammation, apoptosis, and fibrosis. Pxdn and Gpx1 are the hub genes for these shared DEGs. Pxdn knockdown reversed the TGF-β-induced increase in HSC activity and markers (Col I, α-SMA, and FN), an effect that was rescued by Gpx1 knockdown. Pxdn knockdown increased GPX1 levels in HSCs, whereas Gpx1 knockdown had no effect on PXDN. In conclusion, Pxdn knockdown attenuated TGF-β-induced activation of HSC by upregulating GPX1. These findings nominate the PXDN-GPX1 axis as a mechanistic candidate warranting in vivo interrogation.