Multi‐omics analysis reveals a crosstalk between ferroptosis and peroxisomes on steatotic graft failure after liver transplantation

Abstract To identify the mechanism underlying macrosteatosis (MaS)‐related graft failure (GF) in liver transplantation (LT) by multi‐omics network analysis. The transcriptome and metabolome were assayed in graft and recipient plasma in discovery ( n = 68) and validation ( n = 89) cohorts. Differentially expressed molecules were identified by MaS and GF status. Transcriptional regulatory networks were generated to explore the mechanism for MaS‐related inferior post‐transplant prognosis. The differentially expressed molecules associated with MaS and GF were enriched in ferroptosis and peroxisome‐related pathways. Core features of MaS‐related GF were presented on decreased transferrin and impaired anti‐oxidative capacity dependent upon dysregulation of transcription factors hepatocyte nuclear factor 4A (HNF4A) and hypoxia‐inducible factor 1A (HIF1A). Furthermore, miR‐362‐3p and miR‐299‐5p inhibited transferrin and HIF1A expression, respectively. Lower M2 macrophages but higher memory CD4 T cells were observed in MaS‐related GF cases. These results were validated in clinical specimens and cellular models. Systemic analysis of multi‐omics data depicted a panorama of biological pathways deregulated in MaS‐related GF. Transcriptional regulatory networks centered on transferrin and anti‐oxidant responses were associated with poor MaS graft quality, qualifying as potential targets to improve prognosis of patients after LT.