HBV upregulates TNNT1 expression through PI3K/AKT/mTOR-c-Myc axis, which in turn induces EMT and liver fibrosis in mice.

Hepatitis B virus (HBV) infection is a major etiological factor in the development of hepatocellular carcinoma (HCC). Despite extensive research efforts, the precise molecular mechanisms and critical host factors driving HBV-induced epithelial-mesenchymal transition (EMT), liver fibrosis and hepatocarcinogenesis remain to be explored. Emerging evidence has identified aberrant expression of Troponin T1 (TNNT1) in malignancies, implicating its potential role in HCC progression. However, the specific role and mechanism of TNNT1 in HBV-associated HCC remain elusive. In this study, we demonstrate that TNNT1 expression is markedly upregulated in HBV-positive HCC tissues, HBV infection/replication cell models and AAV-HBV1.3-infected mouse models. Mechanistically, HBV activates the transcription factor c-Myc via the PI3K/AKT/mTOR signaling pathway. HBV promotes HCC cell proliferation and EMT markers (Cyclin D1, Vimentin increased, E-cadherin decreased) and liver fibrosis marker α-smooth muscle actin (α-SMA) expression in a TNNT1-dependent manner. HBV infection-induced EMT and liver fibrosis can be abolished by hepatic-specific TNNT1 knockout or knockdown in mice. These findings provide novel insights into the role of TNNT1 in HBV-driven EMT and liver fibrosis, and establish a foundation for further exploration of TNNT1 as a potential therapeutic target in HBV-associated HCC progress.