[Exploring the protective effects and mechanisms of HYX1-derived exosomes on acute liver failure based on disulfidptosis signaling].

Objective: To explore the protective effect and molecular mechanism of human liver stem cell line HYX1-derived exosomes (HYX1-Exos) on acute liver failure (ALF) based on disulfidptosis signaling. Methods: Healthy male BALB/c mice were intraperitoneally injected with D-galactosamine/lipopolysaccharide (D-GalN/LPS) to induce ALF. Mice were divided into a normal control group, an acute liver failure group (ALF group), a disulfidptosis inhibitor tris (2-carboxyethyl) phosphine (TCEP) intervention group (TCEP+ALF group), a HYX1-Exos intervention group (HYX1-Exos+ALF group), and a SLC7A11-IN-1 intervention group (SLC7A11-IN-1+ALF group), with five mice per group. Blood and liver tissue samples were collected. The degree of liver tissue damage was assessed based on serum transaminase levels and hematoxylin-eosin staining results. Quantitative PCR was used to analyze the gene expression levels of disulfidptosis markers SLC7A11, GLUT1, and WAVE2 in liver tissues of each group. Cell Counting Kit-8 (CCK-8) was used to evaluate hepatocyte viability. Statistical analysis was performed using the independent samples t-test and one-way ANOVA. Results: TCEP treatment had significantly alleviated liver damage in ALF mice, as indicated by a marked reduction in transaminase levels [alanine aminotransferase: (312.01±19.46) U/L vs. (1 512.09±229.34) U/L, t=10.38, P<0.001; aspartate aminotransferase: (76.30±39.63) U/L vs. (324.17±78.27) U/L, t=5.75, P<0.001] and a notable improvement in liver histology. HYX1-Exos treatment had significantly reduced liver injury and disulfidptosis levels in ALF mice. Liver injury and disulfidptosis levels were significantly reduced with inhibition of SLC7A11 in ALF mice. In vitro experiments showed that HYX1-Exos protected hepatocytes from disulfidptosis induced by high SLC7A11 under glucose starvation. Conclusion: Disulfidptosis plays an important role in the development of ALF, and HYX1-Exos likely have a hepatoprotective effect on ALF by inhibiting SLC7A11-mediated disulfidptosis.