PR/SET domain 1 targeting glutathione peroxidase 4 regulates chronic hepatitis B liver fibrosis through ferroptosis.

Objective: Addressing the inhibition and reversal of chronic hepatitis B fibrosis is an urgent global challenge, which highlights the critical need to understand its underlying mechanisms. Inhibiting the activation of hepatic stellate cells (HSCs) is an important strategy for fibrosis reversal. In particular, the induction of ferroptosis in HSCs presents a promising avenue for curtailing liver fibrosis. Therefore, this study explores the influence of PR/SET domain 1 (PRDM1), which is a transcriptional regulator, on the progression of liver fibrosis by regulating HSC ferroptosis through glutathione peroxidase 4 (GPX4). Material and Methods: We used protein-protein interaction databases to analyze the interacting proteins of GPX4. The messenger ribonucleic acid levels of PRDM1 and GPX4 in liver tissues with varying degrees of fibrosis were examined using quantitative polymerase chain reaction. Cell lines with interference and overexpression of PRDM1/GPX4 were established. Reactive oxygen species (ROS) activity, malondialdehyde (MDA) concentration, cell proliferation capacity, as well as the expression levels of GPX4, a-smooth muscle actin, vimentin, and desmin, were assessed to investigate the relationship between PRDM1 and hepatic fibrosis, as well as its impact on ferroptosis in HSCs. Results: A significant negative correlation was observed between the transcriptional regulator PRDM1 and GPX4. As the degree of fibrosis worsened, PRDM1 decreased significantly, whereas GPX4 increased significantly. The overexpression of PRDM1 markedly increased ROS and MDA concentrations, but it decreased cell proliferation capacity, GPX4 expression levels, and activation marker protein levels. Interference with PRDM1 yielded opposite results. The expression level of GPX4 did not affect PRMD1 expression levels. Compared with cells with single interference of PRDM1, simultaneous interference with PRDM1 and GPX4 significantly inhibited the activity and proliferation capacity of HSCs. It also elevated ROS activity and MDA concentrations. When ferroptosis inhibitors were added, ROS activity and MDA concentrations decreased, and the proliferation capacity and activity of HSCs increased. Opposite results were obtained when PRDM1 and GPX4 were overexpressed simultaneously. Conclusion: PRDM1 is implicated in the occurrence and progression of hepatic fibrosis. It may act as an upstream regulatory factor of GPX4, which exerts control over ferroptosis by suppressing the transcription of GPX4. Ultimately, the activation of HSCs is promoted.