Hepatitis B virus X protein stabilizes TPM1 to epigenetically inhibit ALDH2 and drive liver cancer progression

As a major viral oncogenic factor, the hepatitis B virus (HBV) X protein (HBx) critically contributes to the malignant progression of liver cancer (LC). Although cytoskeletal proteins are implicated in HBx-mediated tumorigenesis, their specific functions and underlying mechanisms in HBx-associated LC remain largely underexplored. Here, we identified that tropomyosin 1 (TPM1), an actin-binding cytoskeletal protein, is significantly overexpressed in HBx-positive LC cells and HBV-associated tumor tissues. Both in vitro and in vivo experiments demonstrated that TPM1 contributes to HBx-induced growth and migration of LC cells. Furthermore, HBx can stabilize TPM1 by disrupting its interaction with SYVN1, an E3 ubiquitin ligase. Additionally, aldehyde dehydrogenase 2 (ALDH2) was identified as a key downstream effector of TPM1. TPM1 markedly downregulates ALDH2 expression, leading to cholesterol accumulation. Specifically, TPM1 binds to histone deacetylase 2 (HDAC2), an epigenetic coregulator, and represses ALDH2 transcription by reducing histone acetylation at the ALDH2 promoter region. Interestingly, HBx enhances the interaction of TPM1with HDAC2, resulting in greater downregulation of ALDH2. Through high-throughput virtual screening and experimental validation, dihydroergotamine mesylate was further identified as a specific TPM1 inhibitor. This compound exerted potent antitumor effects by counteracting HBx-induced cholesterol accumulation and oncogenic phenotypes in LC cells. Collectively, these results delineate a mechanism by which the cytoskeletal protein TPM1 facilitates HBx-induced hepatocarcinogenesis and highlight TPM1 as a promising therapeutic target for HBV-positive LC. suppressing histone acetylation. DHE, a newly identified inhibitor of TPM1, restrains HBx-mediated LC cell biological behaviors. Graphical Abstract A schematic illustration of HBx upregulating TPM1 to inhibit ALDH2 and increase cholesterol accumulation, LC cell proliferation, and migration. HBx promotes TPM1 stabilization by inhibiting SYVN1-mediated ubiquitination-dependent degradation of TPM1. HBx enhances TPM1’s interaction with HDAC2 to suppress ALDH2 gene transcription by suppressing histone acetylation. DHE, a newly identified inhibitor of TPM1, restrains HBx-mediated LC cell biological behaviors.