HBV activates hepatic stellate cells through RUNX2/ITGBL1 axis

Background
Chronic hepatitis B (CHB) continues to pose a major global health burden, with liver fibrosis representing a pivotal factor in the progression of the disease. Although antiviral therapies can suppress viral replication, many CHB patients continue to experience fibrosis, underscoring the need for novel biomarkers and therapeutic strategies. This study explores the molecular mechanisms driving HBV-induced liver fibrosis, with a particular focus on the transcription factor RUNX2 and its regulation of integrin beta-like 1 (ITGBL1), a protein implicated in fibrogenesis.

Methods
To elucidate the role of RUNX2 in liver fibrosis, we analyzed its relationship with ITGBL1 using both in vitro hepatocyte models and an in vivo HBV-infected mouse model. Chromatin immunoprecipitation (ChIP) assays, luciferase reporter assays, and Western blot analysis were employed to determine the binding of RUNX2 to the ITGBL1 promoter and to evaluate its influence on ITGBL1 expression. Furthermore, we investigated the effects of RUNX2 inhibition using Vitamin D3 and the small-molecule inhibitor CADD522 on ITGBL1 expression and hepatic stellate cell activation.

Results
Our results demonstrate that RUNX2 directly binds to the promoter region of ITGBL1, upregulating its expression and driving the activation of hepatic stellate cells—a key event in fibrogenesis. HBV infection markedly increased the expression of both RUNX2 and ITGBL1 in hepatocytes. Pharmacological inhibition of RUNX2 using Vitamin D3 or CADD522 significantly suppressed ITGBL1 expression and prevented hepatic stellate cell activation. These findings suggest that the RUNX2–ITGBL1 signaling axis is a central mediator in HBV-induced liver fibrosis.

Conclusions
RUNX2 contributes to liver fibrosis in the context of chronic hepatitis B by transcriptionally upregulating ITGBL1, thereby promoting fibrotic responses. Targeting RUNX2 may offer a promising therapeutic avenue to reduce or prevent liver fibrosis in patients with CHB.