Spatiotemporal Transcriptomics Characterizes Immune Microenvironment During Mouse Liver Aging

The liver is a major metabolic organ, responsible for synthesizing and breaking down diverse metabolites. Recently, the liver's immunological functions have gradually been unveiled: combating pathogens and maintaining tissue homeostasis. Age-related functional alterations in these immune cells emerge as potential drivers of hepatic dysfunction and age-associated pathologies. However, systematic investigations into spatiotemporal immune cell dynamics during liver aging remain limited. To address this gap, we analyzed young and old mouse livers using single-cell/nuclei and spatial transcriptomics, revealing T cells as the immune cell population with the most pronounced transcriptomic alterations, marked by enrichment of exhausted CD8⁺ T cells in aged livers. Spatial mapping showed exhausted CD8⁺ T cells accumulating in portal vein (PV) zone, co-localizing with periportal hepatocytes (PP hepatocytes). Up-regulation of LPIN1 in PP hepatocyte promoted T cell exhaustion. CD8⁺ T cell exhaustion was tightly associated with disease progression. Therefore, our findings suggest that targeting LPIN1 may alleviate T cell exhaustion, offering potential therapeutic strategies for age-related liver diseases.