IFRD1 orchestrates hepatocyte metabolism and macrophage interactions to facilitate liver regeneration [scRNA-Seq]

Background & Aims Liver regeneration is a tightly regulated process requiring coordinated interactions between hepatocytes and non-parenchymal cells; however, its molecular mechanisms remain incompletely defined. Here, we aimed to investigate the role of interferon-related developmental regulator 1 (IFRD1) in regulating metabolic–immune crosstalk during liver regeneration. Methods We integrated public transcriptomic datasets, human liver disease samples, and multiple in-house–generated experimental models to characterize the dynamic expression of IFRD1 during liver regeneration. Genetic loss-of-function approaches, including global and cell type–specific knockout mice, together with adeno-associated virus–mediated gain-of-function strategies, were combined with single-nucleus RNA-seq, ATAC-seq, metabolic and biochemical assays, protein interaction analyses, and in vivo rescue experiments to elucidate the underlying mechanisms and clinical relevance. Results Hepatocyte IFRD1 was rapidly induced during the early phase of liver regeneration in mice but markedly diminished in human chronic liver disease. Hepatocyte-specific loss of IFRD1 impaired liver repair and regeneration, whereas IFRD1 overexpression enhanced regenerative responses across multiple models, including partial hepatectomy, toxic liver injury, and hepatic ischemia–reperfusion injury. Mechanistically, IFRD1 was required to sustain hepatocyte β-oxidation and mitochondrial ATP production by stabilizing SLC25A5 through competition with the E3 ubiquitin ligase TRIM21. This ATP boost enables chromatin remodeling in hepatocytes, promoting CCL/CXC chemokine expression to recruit CCR2+ monocytes and expand the regenerative GPNMB+ macrophage pool. Notably, IFRD1 overexpression restored liver regenerative capacity after partial hepatectomy in mice with metabolic dysfunction–associated steatohepatitis or DEN-induced liver fibrosis. Conclusions Our findings define IFRD1 as a key immunometabolic regulator of liver regeneration, mediating hepatocyte metabolic control to macrophage-driven regenerative responses, and support the therapeutic potential of targeting IFRD1 to enhance regenerative capacity in liver disease.