IFRD1 orchestrates hepatocyte metabolism and macrophage interactions to facilitate liver regeneration

Abstract

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.

Impact and implications: Liver regeneration is essential for recovery from surgical resection and acute injury, yet therapeutic options to enhance this process remain limited. Our study identifies the IFRD1-SLC25A5-ATP axis as a critical regulator that coordinates hepatocyte energy metabolism with expansion of pro-regenerative macrophage pool. This previously unrecognized regulatory node provides a scientific rationale for developing therapeutic strategies that enhance IFRD1 function to accelerate liver repair. Although limitations remain, such as undefined upstream regulators of IFRD1, these findings provide a foundation for developing improved therapies for patients with compromised regenerative capacity.

Keywords: APAP; GPNMB; Hepatectomy; Hepatic ischemia–reperfusion injury; Hepatocytes; IFRD1; Lipid associated macrophages; Liver injury; Liver regeneration; Metabolism; Monocyte-Derived Macrophages.