Single-cell transcriptomics uncovers persistent hepatic immunometabolic remodeling following SARS-CoV-2 infection in obese hosts

SARS-CoV-2 infection affects multiple organs, and chronic post-viral tissue injury is often associated with persistent immune dysregulation. Obesity and related metabolic disorders are major risk factors for severe COVID-19 and post-acute sequelae of SARS-CoV-2 infection (PASC), including liver dysfunction. To define hepatic responses during post-acute infection, we studied lean and diet-induced obese mice at 7 and 28 days following infection with mouse-adapted SARS-CoV-2. Compared with lean mice, obese mice exhibited persistent lung inflammation and fibrosis, along with liver injury characterized by increased lipid accumulation, cellular apoptosis, and metabolic dysfunction. Single-cell RNA sequencing revealed obesity-associated alterations in hepatic immune and metabolic programs during post-acute infection. In particular, hepatic macrophages in obese mice showed sustained inflammatory and metabolic transcriptional alterations, while hepatocytes displayed altered programs associated with gluconeogenesis and lipid metabolism. Endothelial cells also exhibited persistent transcriptional changes linked to immune activation and prothrombotic pathways. These alterations remained evident at 28 days post-infection, suggesting incomplete restoration of immune and metabolic homeostasis in obese liver. Collectively, our findings reveal persistent obesity-associated hepatic immunometabolic remodeling following SARS-CoV-2 infection and identify cellular and molecular programs that may contribute to post-acute liver sequelae in metabolically compromised hosts.