Deacetylation of PRDX1 contributes to alleviating acute liver injury through Dihydromyricetin-mediated SIRT1 upregulation.

Abstract

BACKGROUND: Acute liver injury (ALI) is a severe condition characterized by excessive hepatic inflammation and oxidative stress, yet effective therapeutic strategies remain limited. Dihydromyricetin (DMY), a natural flavonoid, possesses hepatoprotective properties, but the precise molecular mechanisms involving acetylation modifications underlying its effects are not fully understood. PURPOSE: The purpose of this study was to investigate the hepatoprotective efficacy of DMY in ALI and to elucidate the specific immunoregulatory mechanisms governing the transition from oxidative stress to inflammatory responses. STUDY DESIGN: A d-galactosamine/lipopolysaccharide-induced murine acute liver injury model was employed to assess the hepatoprotective effect of dihydromyricetin. Quantitative acetylomic profiling combined with single-cell RNA sequencing was used to explore the underlying molecular mechanisms, which were further validated by genetic modulation of SIRT1 and PRDX1 in macrophage cell lines and macrophage-specific SIRT1 overexpression via adeno-associated virus in mice. METHODS: We utilized a d-galactosamine/lipopolysaccharide (DgalN/LPS)-induced murine ALI model to evaluate the therapeutic effect of DMY. The underlying mechanisms were investigated by integrating quantitative acetylomic profiling with single-cell RNA sequencing (scRNA-seq), followed by functional validation through genetic modulation of SIRT1 and PRDX1 in macrophage cell lines, and systemic SIRT1 overexpression mediated by AAV in mice. RESULTS: DMY administration significantly ameliorated liver injury, evidenced by improved survival, reduced serum aminotransferases, and suppressed inflammatory responses. Acetylomic profiling identified Peroxiredoxin 1 (PRDX1) as a key effector, which is hyperacetylated at the conserved lysine 35 (K35) residue during ALI. Mechanistically, DMY restored the expression of Sirtuin 1 (SIRT1), a deacetylase markedly downregulated in hepatic macrophages in both mouse and human ALI. SIRT1 physically interacts with and deacetylates PRDX1 at K35, thereby restoring its antioxidant activity and inhibiting pro-inflammatory M1 macrophage polarization. Notably, SIRT1 overexpression phenocopied the hepatoprotective effects of DMY. CONCLUSION: Our findings identify the SIRT1-PRDX1 axis as a critical immunoregulatory mechanism underlying DMY-mediated hepatoprotection. This study suggests DMY as a promising therapeutic candidate for the treatment of acute liver injury.