Thrombospondin-1 suppresses HBV replication via modulating antiviral immunity and macrophage polarization

Objective Chronic Hepatitis B Virus (HBV) infection is a persistent global health threat, strongly predisposing individuals to cirrhosis and hepatocellular carcinoma (HCC). Although THBS1 is recognized for its immunoregulatory properties, its involvement in HBV pathogenesis and subsequent liver disease is not fully elucidated. Methods Circulating THBS1 levels were measured in patients during the immune clearance phase of HBV infection. Serum analysis included 21 healthy controls and 59 HBV patients across predefined phases.THBS1 expression and its correlation with immune cell infiltration were analyzed in general HCC datasets. In vitro assays assessed THBS1 in M1-like macrophage polarization using Huh7/HepG2 HBV-replication models and THP-1-derived macrophages.Additionally, in vivo experiments were conducted using a HBV-replicating mouse model(n = 10 per group) with enforced THBS1 expression to evaluate its effect on hepatic HBV replication. Results Our initial investigation revealed a marked elevation in circulating THBS1 levels in patients undergoing the immune clearance phase of HBV infection. Despite being generally down-regulated in HCC tissues, THBS1 expression displayed a positive association with the extent of immune cell infiltration, indicating a complex functional duality. Functionally, THBS1 knockdown reduced M1-like markers in vitro. Most importantly, in a HBV-replicating mouse model, enforced expression of THBS1 was associated with reduced hepatic HBV replication. Conclusion Overall, our findings indicate that THBS1 is induced during the antiviral response, is associated with M1-like polarization, and possesses antiviral effects in engineered overexpression models. This phase-dependent action positions THBS1 as a candidate pathway requiring further validation in HBV-related liver disease.