Quercetin alleviates ethanol-induced hepatocyte senescence by interacting with glycinamide ribonucleotide transformylase.

Quercetin demonstrates therapeutic potential for alcoholic liver disease. However, its precise molecular targets and mechanisms of action require further elucidation. This research aimed to systematically investigate its hepatoprotective mechanisms using transcriptomic and metabolomic analyses. Initially, mice fed a Lieber-DeCarli diet containing 5 % (v/v) ethanol and quercetin (100 mg/kg·bw) exhibited decreased triglyceride level, serum aminotransferase concentration, and hepatic lipid droplet accumulation. Additionally, integrated analysis of transcriptomic and metabolomic revealed significant enrichment in purine metabolic pathway, which supplies substrates for the S-phase of the cell cycle. Notably, the purine intermediate 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) was identified as the most prominently altered one under quercetin treatment (VIP = 4.237, P < 0.05). AICAR administration abrogated the anti-senescent effects of quercetin in hepatocytes, evidenced by increased SA-β-gal+ cells and elevated senescent marker (p53, p21, and p16) expression. Moreover, human proteome microarray screening and cellular thermal shift assays revealed that glycinamide ribonucleotide transformylase (GART), a rate-limiting enzyme in AICAR biosynthesis, has potential to bind with quercetin. The overexpression of GART completely negated quercetin's capacity to suppress hepatocyte senescence. In conclusion, quercetin alleviates ethanol-induced hepatocyte senescence by interacting with GART, thereby providing insights into its pharmacological action on alcoholic liver disease.