Serine Glycine Restriction Aggravates Hepatic Ischemia-reperfusion Injury.

BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) significantly affects liver function in liver transplantation, primarily through dysregulated metabolism and inflammation. Although serine and glycine (SG) have been identified as potential therapeutic targets in various diseases, the mechanisms by which SG influences HIRI remain unclear. This study aimed to investigate the effects of SG deficient (-SG) dietary intervention on HIRI. METHODS: We established an in vivo and in vitro HIRI model under the -SG condition. RNA sequencing, coupled with bioinformatics analysis, identified key targets modulated after -SG intervention. Biochemical and histological analyses were used to evaluate the effects of -SG on HIRI. Furthermore, plasmid-based transient overexpression of CYP2S1 and CYP26B1 was induced to explore the mechanistic role of -SG in regulating cell apoptosis and inflammatory responses. RESULTS: Histological and liver enzyme analyses confirmed that SG deficiency worsened ischemia-reperfusion-induced liver necrosis and impaired liver function. Furthermore, SG deficiency exacerbated hepatocyte apoptosis, immune responses, and inflammatory responses caused by ischemia-reperfusion injury in vivo and in vitro experiments. RNA sequencing revealed a correlation between CYP family signaling pathway and liver injury resulting from SG deficiency. CONCLUSIONS: SG deficiency exacerbated apoptosis, as well as immune and inflammatory responses in a liver injury model. The lack of these amino acids can promote inflammation and worsen HIRI by downregulating CYP2S1 and CYP26B1 expression. Conversely, SG supplementation may exhibit a protective effect against liver injury after transplantation.