Brg1 interacts with liver X receptor and H3K18la to regulate ferroptosis via the CYP4A14/20-HETE axis in liver transplantation

Liver transplantation is the definitive therapy for end-stage liver disease, but ischemia-reperfusion injury (IRI) remains a major cause of graft dysfunction. The chromatin remodeling protein Brahma-related gene 1 (Brg1) has been implicated in liver pathophysiology, yet its role in liver transplantation IRI and Ferroptosis remains unclear. In this study, human graft biopsies were conducted and a mouse liver transplantation model was developed. RNA-seq, targeted metabolomics, and in vitro oxygen-glucose deprivation/reoxygenation assays explored underlying mechanisms. Coimmunoprecipitation and chromatin immunoprecipitation were performed to assess Brg1 interactions with transcriptional regulators. Brg1 was markedly upregulated in human and mouse grafts after liver transplantation, correlating with posttransplant liver injury. Hepatocyte-specific Brg1 knockout alleviates IRI and Ferroptosis by suppressing CYP4A14 transcription and 20-HETE production. In vitro, Brg1 knockdown protected hepatocytes from oxygen-glucose deprivation/reoxygenation-induced injury and Ferroptosis, whereas reintroduction of CYP4A14 or 20-hydroxyeicosatetraenoic acid (20-HETE) restored this injury. In summary, this study identified Brg1 as a key driver of liver transplantation IRI and Ferroptosis. Mechanistically, Brg1 interacts with liver X receptor and H3K18la to promote CYP4A14 transcription, thereby enhancing ω-hydroxylation of arachidonic acid to generate 20-HETE. Our findings may offer a theoretical framework for developing novel clinical strategies to prevent and mitigate IRI in liver transplantation.

Brg1; ferroptosis; ischemia-reperfusion injury; liver transplantation.